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1. MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression

Author

Yao Jiang, Yanqiong Zhang, Janet Y. Leung, Cheng Fan, Konstantin I. Popov, Siyuan Su, Jiayi Qian, Xiaodong Wang, Alisha Holtzhausen, Eric Ubil, Yang Xiang, Ian Davis, Nikolay V. Dokholyan, Gang Wu, Charles M. Perou, William Y. Kim, H. Shelton Earp, and Pengda Liu

Subjects
Science
Abstract

Hyperactivation of Akt promotes tumorigenesis. Here, the authors show that SAV1, a member of Hippo signalling, interacts with Akt to suppress Akt activity and MERTK-mediated Akt phosphorylation relieves this suppression to facilitate Akt oncogenic activity in clear cell renal carcinomas.

Published
2019
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2. Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy

Author

Nicholas C. DeVito, Michael Sturdivant, Balamayooran Thievanthiran, Christine Xiao, Michael P. Plebanek, April K.S. Salama, Georgia M. Beasley, Alisha Holtzhausen, Veronica Novotny-Diermayr, John H. Strickler, and Brent A. Hanks

Subjects
Wnt-β-catenin pathway, anti-PD-1 resistance, dendritic cells, regulatory T cells, myeloid-deriver suppressor cells, indoleamine 2,3-dioxygenase, Biology (General), QH301-705.5
Abstract

Summary: While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.

Published
2021
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3. Factor XIIIA—expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking

Author

Alessandro Porrello, Patrick L. Leslie, Emily B. Harrison, Balachandra K. Gorentla, Sravya Kattula, Subrata K. Ghosh, Salma H. Azam, Alisha Holtzhausen, Yvonne L. Chao, Michele C. Hayward, Trent A. Waugh, Sanggyu Bae, Virginia Godfrey, Scott H. Randell, Cecilia Oderup, Liza Makowski, Jared Weiss, Matthew D. Wilkerson, D. Neil Hayes, H. Shelton Earp, Albert S. Baldwin, Alisa S. Wolberg, and Chad V. Pecot

Subjects
Science
Abstract

Lung squamous carcinomas (LUSC) are poorly molecularly characterized, but sub-populations show promising response to immune checkpoint inhibitors. Here, the authors identify a subset of LUSC characterized by infiltration of inflammatory monocytes, where metastasis is linked to Factor XIIIA promoting fibrin cross-linking.

Published
2018
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6. Data from TAM Family Receptor Kinase Inhibition Reverses MDSC-Mediated Suppression and Augments Anti–PD-1 Therapy in Melanoma

Author

H. Shelton Earp, Stephen V. Frye, Douglas K. Graham, Xiaodong Wang, Qingyang Liu, Dehui Zhang, Yuewei Zhang, Jichen Zhao, Debra M. Hunter, Eric Ubil, William Harris, and Alisha Holtzhausen

Abstract

Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)>20-fold, polymorphonuclear MDSCs (PMN-MDSC)>15-fold] in tumor-bearing mice. MDSCs from tumor-bearing Mertk−/−, Axl−/−, and Tyro3−/− mice exhibited diminished suppressive enzymatic capabilities, displayed deficits in T-cell suppression, and migrated poorly to tumor-draining lymph nodes. In coimplantation experiments using TYRO3−/−, AXL−/−, and MERTK−/− MDSCs, we showed the absence of these RTKs reversed the protumorigenic properties of MDSCs in vivo. Consistent with these findings, in vivo pharmacologic TYRO3, AXL, and MERTK inhibition diminished MDSC suppressive capability, slowed tumor growth, increased CD8+ T-cell infiltration, and augmented anti–PD-1 checkpoint inhibitor immunotherapy. Mechanistically, MERTK regulated MDSC suppression and differentiation in part through regulation of STAT3 serine phosphorylation and nuclear localization. Analysis of metastatic melanoma patients demonstrated an enrichment of circulating MERTK+ and TYRO3+ M-MDSCs, PMN-MDSCs, and early-stage MDSCs (e-MDSC) relative to these MDSC populations in healthy controls. These studies demonstrated that TYRO3, AXL, and MERTK control MDSC functionality and serve as promising pharmacologic targets for regulating MDSC-mediated immune suppression in cancer patients.

Published
2023
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8. Data from Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy

Author

Brent A. Hanks, Douglas S. Tyler, Ciriana Orabona, Masahito Tsutsui, Kathy S. Evans, Fei Zhao, and Alisha Holtzhausen

Abstract

The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane–bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti–CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node–derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt–β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy. Cancer Immunol Res; 3(9); 1082–95. ©2015 AACR.

Published
2023
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10. Data from Stromal Fibroblasts Mediate Anti–PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma

Author

Brent A. Hanks, Gerard C. Blobe, Peter J. Siska, Alisha Holtzhausen, Balamayooran Theivanthiran, Nicholas DeVito, Christine Xiao, Kathy Evans, and Fei Zhao

Abstract

Although anti–PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacologic inhibition of the TGFβ signaling pathway synergistically enhanced the efficacy of anti–CTLA-4 immunotherapy but failed to augment anti–PD-1/PD-L1 responses in an autochthonous model of BRAFV600E melanoma. Additional mechanistic studies revealed that TGFβ pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby facilitating MMP-9–dependent cleavage of PD-L1 surface expression, leading to anti–PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti–PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGFβ signaling activity. Delayed TGFβ inhibitor therapy, following anti–PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti–PD-1 and TGFβ inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti–PD-1 and suggests that TGFβ inhibition may generate greater immunologic efficacy when administered following the development of acquired anti–PD-1 resistance.See related Spotlight on p. 1444

Published
2023
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11. Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy

Author

Balamayooran Theivanthiran, Nagendra Yarla, Tarek Haykal, Y.-Van Nguyen, Linda Cao, Michelle Ferreira, Alisha Holtzhausen, Rami Al-Rohil, April K.S. Salama, Georgia M. Beasley, Michael P. Plebanek, Nicholas C. DeVito, and Brent A. Hanks

Subjects
Toll-Like Receptor 4, NLR Family, Pyrin Domain-Containing 3 Protein, Disease Progression, Tumor Microenvironment, Humans, HSP70 Heat-Shock Proteins, General Medicine, Immunotherapy, Melanoma
Abstract

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome–heat shock protein 70 (HSP70) signaling axis is triggered by CD8 + T cell cytotoxicity and contributes to the development of adaptive resistance to anti–programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti–PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti–PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti–PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti–PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.

Published
2022

12. Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events

Author

Cameron J. Oswalt, Rami N. Al-Rohil, Bala Theivanthiran, Tarek Haykal, April K.S. Salama, Nicholas C. DeVito, Alisha Holtzhausen, Dennis C. Ko, and Brent A. Hanks

Subjects
Pharmacology, Cancer Research, Antineoplastic Agents, Immunological, Immunology, Immunology and Allergy, Humans, Neoplasms, Second Primary, Immunotherapy, Pyrin, Melanoma
Abstract

The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs.

Published
2021

13. Abstract B45: Loss of MerTK and Tyro3, but not Axl, substantially reverses the immune-suppressive tumor microenvironment in a syngeneic pancreatic cancer model

Author

Nancy Kren, Alisha Holtzhausen, Douglas Graham, Yuliya Pylayeva-Gupta, and H SHELTON EARP

Subjects
Cancer Research, Immunology
Abstract

Tyro3, Axl and MerTK (TAM) are a family of receptor tyrosine kinases (RTKs) that play physiologic roles in dampening innate immune responses, preventing chronic inflammation and autoimmunity. Their roles in potentially promoting tolerance in the immunosuppressive tumor microenvironment (TME) in the context of neoplasia are unclear. Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, a notoriously immune suppressive TME and limited treatment options. Here we evaluate the role of TAM RTKs in the PDAC TME using orthotopic injection of a pancreatic cell line into mertk-/-,axl-/- ,tyro3-/- and mertk-/-/tyro3 double knockout( DKO) mice. The loss of MerTK or Tyro3 in the TME substantially attenuates orthotopic PDAC growth. Moreover, pancreatic tumors implanted in the mertk-/-/tyro3-/- DKO tumors completely regress suggesting that these two RTKs have at least some non-redundant suppressive activities. Furthermore, loss of MerTK or Tyro3 overcame resistance to anti-PD-1 treatment, with most tumors completely regressed. Surprisingly none of these effects are seen in the axl-/- mouse and, in fact ,a metastatic assay showed increased KPC liver metastases in axl-/- mice as compared to WT. In this assay, liver metastases were decreased in tyro3-/- and mertk-/- mice compared to WT mice. This contrasts with data from our lab and others showing that knock down of Axl in the tumor cells themselves diminishes metastatic potential in wild type mice. These data suggest that inhibition of Axl in host infiltrating cells and the tumor cells may have divergent actions in PDAC. Mechanistically, we utilized NanoString to identify significant changes in genes associated with antigen processing and presentation as well as an overall increase in immune response in mertk-/- mice. However, NanoString RNA expression data highlighted distinct signaling pathways in tumor bearing-tyro3-/- mice, again suggesting that the similar endpoint phenotypes (attenuated growth) are brought about by at least some non-redundant mechanisms. The growth attenuation in the mertk-/- and tyro3-/- is lost with antibody depletion of CD8a cells indicating the final common mechanism for MerTK or Tyro3 loss is CD8 cell dependent. These data highlight the fact that while these three receptors are often thought of as similar in action, deletion or inhibition may have distinct mechanisms or effects in the TME. These data also suggest that MerTK or Tyro3 targeted therapy in combination with anti-PD-1 merits exploration in PDAC; those experiments are ongoing with UNC-developed MerTK-selective inhibitors. Citation Format: Nancy Kren, Alisha Holtzhausen, Douglas Graham, Yuliya Pylayeva-Gupta, H SHELTON EARP. Loss of MerTK and Tyro3, but not Axl, substantially reverses the immune-suppressive tumor microenvironment in a syngeneic pancreatic cancer model [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B45.

Published
2022
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14. Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis

Author

Linda Cao, Tarek Haykal, Alisha Holtzhausen, Brent A. Hanks, Nicholas DeVito, Michael Plebanek, and Balamayooran Theivanthiran

Subjects
granulocytic myeloid-derived suppressor cells, Cancer Research, Tumor microenvironment, Myeloid, Innate immune system, medicine.medical_treatment, adaptive immunotherapy resistance, Cell, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Inflammasome, Immunotherapy, Review, Biology, NLRP3 inflammasome, medicine.anatomical_structure, Oncology, Immunity, medicine, Cancer research, Receptor, RC254-282, HSP70, medicine.drug
Abstract

Simple Summary The tumor-intrinsic NLRP3 inflammasome is a newly recognized player in the regulation of tumor-directed immune responses and promises to provide fresh insight into how tumors respond to immunotherapy. This brief review discusses recent data describing how activation of the tumor-intrinsic NLRP3 inflammasome contributes to immune evasion and what this pathway may provide to the field of immuno-oncology both in terms of pharmacologic targets capable of boosting responses to checkpoint inhibitor therapies and predictive biomarkers indicating which tumors may be most susceptible to these new therapeutic strategies. Abstract The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.

Published
2021

15. Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy

Author

Michael Plebanek, Brent A. Hanks, Michael Sturdivant, Veronica Novotny-Diermayr, Christine Xiao, April K.S. Salama, Nicholas DeVito, Balamayooran Thievanthiran, Georgia M. Beasley, John H. Strickler, and Alisha Holtzhausen

Subjects
0301 basic medicine, indoleamine 2,3-dioxygenase, QH301-705.5, medicine.medical_treatment, Wnt-β-catenin pathway, Wnt1 Protein, Ligands, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Paracrine signalling, Mice, Immune system, 0302 clinical medicine, Tumor Microenvironment, Medicine, Animals, Humans, dendritic cells, Biology (General), myeloid-deriver suppressor cells, Autocrine signalling, anti-PD-1 resistance, Tumor microenvironment, business.industry, Wnt signaling pathway, Immunotherapy, Dendritic cell, Immune checkpoint, Blockade, Disease Models, Animal, regulatory T cells, 030104 developmental biology, Cancer research, business, 030217 neurology & neurosurgery
Abstract

SUMMARY While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition., Graphical abstract, In brief Anti-PD-1-refractory melanoma exhibits elevated Wnt ligand signaling activity. DeVito et al. demonstrate that pharmacologic inhibition of proximal Wnt ligand signaling sensitizes transgenic models of melanoma and lung cancer to anti-PD-1 checkpoint inhibitor immunotherapy by reversing dendritic cell tolerization and suppressing recruitment of granulocytic myeloid-derived suppressor cells to the tumor bed.

Published
2020

16. Factor XIIIA—expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking

Author

Balachandra K. Gorentla, Patrick L. Leslie, Trent A. Waugh, D. Neil Hayes, Jared Weiss, Albert S. Baldwin, Emily B. Harrison, Subrata K. Ghosh, Alessandro Porrello, Yvonne L. Chao, Michele C. Hayward, Alisa S. Wolberg, Sravya Kattula, Alisha Holtzhausen, Matthew D. Wilkerson, Cecilia Oderup, Chad V. Pecot, Liza Makowski, Virginia Godfrey, Sanggyu Bae, Scott H. Randell, H. Shelton Earp, and Salma H. Azam

Subjects
Male, 0301 basic medicine, Lung Neoplasms, Science, General Physics and Astronomy, Article, Monocytes, General Biochemistry, Genetics and Molecular Biology, Fibrin, Metastasis, Mice, 03 medical and health sciences, Biomarkers, Tumor, Carcinoma, medicine, Animals, Humans, Neoplasm Invasiveness, lcsh:Science, Lung cancer, Chemokine CCL2, Regulation of gene expression, Multidisciplinary, Lung, biology, business.industry, General Chemistry, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Mice, Inbred DBA, Carcinoma, Squamous Cell, Cancer research, biology.protein, Female, lcsh:Q, Factor XIIIa, business, Infiltration (medical)
Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. Molecular aberrations in lung adenocarcinomas have allowed for effective targeted treatments, but corresponding therapeutic advances in LUSC have not materialized. However, immune checkpoint inhibitors in sub-populations of LUSC patients have led to exciting responses. Using computational analyses of The Cancer Genome Atlas, we identified a subset of LUSC tumors characterized by dense infiltration of inflammatory monocytes (IMs) and poor survival. With novel, immunocompetent metastasis models, we demonstrated that tumor cell derived CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Pharmacologic inhibition of IM recruitment had substantial anti-metastatic effects. Notably, we show that IMs highly express Factor XIIIA, which promotes fibrin cross-linking to create a scaffold for LUSC cell invasion and metastases. Consistently, human LUSC samples containing extensive cross-linked fibrin in the microenvironment correlated with poor survival., Lung squamous carcinomas (LUSC) are poorly molecularly characterized, but sub-populations show promising response to immune checkpoint inhibitors. Here, the authors identify a subset of LUSC characterized by infiltration of inflammatory monocytes, where metastasis is linked to Factor XIIIA promoting fibrin cross-linking.

Published
2018

17. A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy

Author

Yubin Kang, Douglas B. Johnson, April K.S. Salama, Balamayooran Theivanthiran, Andrew B. Nixon, Mark D. Starr, Lucas P. Wachsmuth, Michael Sturdivant, David Hsu, Alisha Holtzhausen, Brent A. Hanks, Kathy Evans, Michael Plebanek, Justin M. Balko, and Nicholas DeVito

Subjects
0301 basic medicine, Male, Inflammasomes, T cell, medicine.medical_treatment, Melanoma, Experimental, CD8-Positive T-Lymphocytes, B7-H1 Antigen, Translational Research, Biomedical, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Cancer immunotherapy, PD-L1, Cell Line, Tumor, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Tumor Microenvironment, Animals, Humans, Melanoma, Mice, Knockout, Innate immune system, biology, business.industry, Myeloid-Derived Suppressor Cells, Models, Immunological, Inflammasome, General Medicine, Immunotherapy, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, Tumor Escape, Signal transduction, business, medicine.drug, Signal Transduction, Research Article
Abstract

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8(+) T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain–containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti–PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti–PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

Published
2019

18. TAM Family Receptor kinase inhibition reverses MDSC-mediated suppression and augments anti-PD-1 therapy in melanoma

Author

Yuewei Zhang, Jichen Zhao, William T. Harris, Dehui Zhang, Douglas K. Graham, Qingyang Liu, Debra Hunter, H. Shelton Earp, Stephen V. Frye, Eric Ubil, Xiaodong Wang, and Alisha Holtzhausen

Subjects
0301 basic medicine, Adult, Male, Cancer Research, Adolescent, medicine.medical_treatment, Immunology, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Receptor tyrosine kinase, Article, 03 medical and health sciences, Mice, Young Adult, 0302 clinical medicine, Antineoplastic Agents, Immunological, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Tumor Microenvironment, Animals, Humans, STAT3, Melanoma, Aged, Aged, 80 and over, Mice, Knockout, Tumor microenvironment, biology, c-Mer Tyrosine Kinase, Chemistry, GAS6, Myeloid-Derived Suppressor Cells, Receptor Protein-Tyrosine Kinases, Immunotherapy, MERTK, Middle Aged, Axl Receptor Tyrosine Kinase, Healthy Volunteers, Mice, Inbred C57BL, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female, Tyrosine kinase, TYRO3
Abstract

Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)>20-fold, polymorphonuclear MDSCs (PMN-MDSC)>15-fold] in tumor-bearing mice. MDSCs from tumor-bearing Mertk−/−, Axl−/−, and Tyro3−/− mice exhibited diminished suppressive enzymatic capabilities, displayed deficits in T-cell suppression, and migrated poorly to tumor-draining lymph nodes. In coimplantation experiments using TYRO3−/−, AXL−/−, and MERTK−/− MDSCs, we showed the absence of these RTKs reversed the protumorigenic properties of MDSCs in vivo. Consistent with these findings, in vivo pharmacologic TYRO3, AXL, and MERTK inhibition diminished MDSC suppressive capability, slowed tumor growth, increased CD8+ T-cell infiltration, and augmented anti–PD-1 checkpoint inhibitor immunotherapy. Mechanistically, MERTK regulated MDSC suppression and differentiation in part through regulation of STAT3 serine phosphorylation and nuclear localization. Analysis of metastatic melanoma patients demonstrated an enrichment of circulating MERTK+ and TYRO3+ M-MDSCs, PMN-MDSCs, and early-stage MDSCs (e-MDSC) relative to these MDSC populations in healthy controls. These studies demonstrated that TYRO3, AXL, and MERTK control MDSC functionality and serve as promising pharmacologic targets for regulating MDSC-mediated immune suppression in cancer patients.

Published
2019

19. Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response

Author

Charlotte Story, H. Shelton Earp, Debra Hunter, Eric Ubil, Laura S. Caskey, and Alisha Holtzhausen

Subjects
0301 basic medicine, medicine.medical_treatment, Receptor tyrosine kinase, B7-H1 Antigen, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Immune system, medicine, Animals, Humans, Mice, Knockout, Innate immune system, Cytokine Suppression, Membrane Glycoproteins, biology, Chemistry, Macrophages, Calcium-Binding Proteins, Imidazoles, General Medicine, TLR7, Immunotherapy, Neoplasms, Experimental, 030104 developmental biology, Cytokine, Toll-Like Receptor 7, Toll-Like Receptor 8, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Cytokines, Resiquimod, Carrier Proteins, Research Article
Abstract

Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor cells with CRISPR-based deletion of Pros1 failed to inhibit M1 polarization. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice. In addition, several other murine and human tumor cell lines suppressed macrophage M1 cytokine expression induced by IFN-γ and LPS. Investigation of the suppressive pathway demonstrated a role for PTP1b complexing with Mer. Substantiating the role of PTP1b, M1 cytokine suppression was also lost in macrophages from PTP1b-KO mice. Mice bearing Pros1-deficient tumors showed increased innate and adaptive immune infiltration, as well as increased median survival. TAM activation can also inhibit TLR-mediated M1 polarization. Treatment with resiquimod, a TLR7/8 agonist, did not improve survival in mice bearing Pros1-secreting tumors but doubled survival for Pros1-deleted tumors. The tumor-derived Pros1 immune suppressive system, like PD-L1, was cytokine responsive, with IFN-γ inducing Pros1 transcription and secretion. Inhibition of Pros1/TAM interaction represents a potential novel strategy to block tumor-derived immune suppression.

Published
2018

20. Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy

Author

Alisha Holtzhausen, Fei Zhao, Ciriana Orabona, Brent A. Hanks, Masahito Tsutsui, Kathy Evans, and Douglas S. Tyler

Subjects
Cancer Research, Cell signaling, Pyridines, medicine.medical_treatment, Immunology, Population, Benzeneacetamides, Mice, Inbred Strains, Mice, Transgenic, chemical and pharmacologic phenomena, Cell Communication, Biology, T-Lymphocytes, Regulatory, Article, Wnt-5a Protein, Immune tolerance, Cell Line, Tumor, Proto-Oncogene Proteins, Immune Tolerance, medicine, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, CTLA-4 Antigen, Molecular Targeted Therapy, education, Melanoma, beta Catenin, education.field_of_study, Wnt signaling pathway, Antibodies, Monoclonal, Membrane Proteins, Dendritic Cells, Immunotherapy, Dendritic cell, medicine.disease, Wnt Proteins, Disease Progression, Cancer research, Lymph Nodes, Signal transduction, Acyltransferases, Neoplasm Transplantation, Signal Transduction
Abstract

The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane–bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti–CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node–derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt–β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy. Cancer Immunol Res; 3(9); 1082–95. ©2015 AACR.

Published
2015
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21. Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma

Author

Gerard C. Blobe, Brent A. Hanks, Nicholas DeVito, Fei Zhao, Peter J. Siska, Christine Xiao, Kathy Evans, Balamayooran Theivanthiran, and Alisha Holtzhausen

Subjects
0301 basic medicine, Male, Proto-Oncogene Proteins B-raf, Cancer Research, Stromal cell, medicine.medical_treatment, Transgene, Immunology, Mice, Transgenic, Matrix metalloproteinase, B7-H1 Antigen, 03 medical and health sciences, Transforming Growth Factor beta, Tumor Microenvironment, Medicine, Animals, CTLA-4 Antigen, Melanoma, Tumor microenvironment, Mice, Inbred BALB C, business.industry, Immunotherapy, Fibroblasts, medicine.disease, Xenograft Model Antitumor Assays, Blockade, Mice, Inbred C57BL, 030104 developmental biology, Matrix Metalloproteinase 9, Drug Resistance, Neoplasm, Cancer research, Quinolines, Pyrazoles, Female, Signal transduction, business
Abstract

Although anti–PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacologic inhibition of the TGFβ signaling pathway synergistically enhanced the efficacy of anti–CTLA-4 immunotherapy but failed to augment anti–PD-1/PD-L1 responses in an autochthonous model of BRAFV600E melanoma. Additional mechanistic studies revealed that TGFβ pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby facilitating MMP-9–dependent cleavage of PD-L1 surface expression, leading to anti–PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti–PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGFβ signaling activity. Delayed TGFβ inhibitor therapy, following anti–PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti–PD-1 and TGFβ inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti–PD-1 and suggests that TGFβ inhibition may generate greater immunologic efficacy when administered following the development of acquired anti–PD-1 resistance. See related Spotlight on p. 1444

Published
2018

22. Paracrine Wnt5a-β-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic Cell Tolerization

Author

Juan Liu, Alisha Holtzhausen, Smita K. Nair, Xiaojing Liu, Brent A. Hanks, Tbalamayooran Theivanthiran, Christine Xiao, Fei Zhao, David Boczkowski, Jason W. Locasale, Nicholas DeVito, and Kathy S. Evans

Subjects
0301 basic medicine, Male, medicine.medical_treatment, Immunology, Immunoblotting, Enzyme-Linked Immunosorbent Assay, Mice, Transgenic, Biology, Polymerase Chain Reaction, Wnt-5a Protein, Article, Cell Line, 03 medical and health sciences, Paracrine signalling, Mice, 0302 clinical medicine, Immune system, Immune privilege, Paracrine Communication, medicine, Immunology and Allergy, Animals, Melanoma, beta Catenin, Tumor microenvironment, Fatty Acids, Interleukin, Dendritic cell, Immunotherapy, Dendritic Cells, Flow Cytometry, PPAR gamma, 030104 developmental biology, Infectious Diseases, 030220 oncology & carcinogenesis, Cancer research, Female, Signal transduction, Signal Transduction
Abstract

Summary Despite recent advances, many cancers remain refractory to available immunotherapeutic strategies. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor microenvironment promotes immune evasion. Here, we have described a mechanism by which melanomas establish a site of immune privilege via a paracrine Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter. This FAO shift increased the protoporphyrin IX prosthetic group of indoleamine 2,3-dioxgenase-1 (IDO) while suppressing interleukin(IL)-6 and IL-12 cytokine expression, culminating in enhanced IDO activity and the generation of regulatory T cells. We demonstrated that blockade of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1 antibody immunotherapy, and suppressed disease progression in a transgenic melanoma model. This work implicates a role for tumor-mediated metabolic reprogramming of local DCs in immune evasion and immunotherapy resistance.

Published
2016

23. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016
Full Text
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24. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. McClanahan, Xinwei Sher, Xiao Qiao Liu, Andrew Joe, Elizabeth Plimack, Alex Forrest-Hay, Cheryl A. Guyre, Kohei Narumiya, Marc Delcommenne, Heather A. Hirsch, Amit Deshpande, Jason Reeves, Jenny Shu, Tong Zi, Jennifer Michaelson, Debbie Law, Elizabeth Trehu, Sriram Sathyanaryanan, Brendan P. Hodkinson, Natalie A. Hutnick, Michael E. Schaffer, Michael Gormley, Tyler Hulett, Carmen Ballesteros-Merino, Christopher Dubay, Michael Afentoulis, Ashok Reddy, Larry David, Kumar Jayant, Swati Agrawal, Rajendra Agrawal, Ghayathri Jeyakumar, Seongho Kim, Heejin Kim, Cynthia Silski, Stacey Suisham, Elisabeth Heath, Ulka Vaishampayan, Natalie Vandeven, Natasja Nielsen Viller, Alison O’Connor, Hui Chen, Bolette Bossen, Eric Sievers, Robert Uger, Lisa Johnson, Hsiang-Fong Kao, Chin-Fu Hsiao, Shu-Chuan Lai, Chun-Wei Wang, Jenq-Yuh Ko, Pei-Jen Lou, Tsai-Jan Lee, Tsang-Wu Liu, Ruey-Long Hong, Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle

Subjects
Pharmacology, 0303 health sciences, Cancer Research, Side effect, business.industry, medicine.drug_class, Immunology, Phases of clinical research, Monoclonal antibody, Phase i study, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Oncology, Pharmacokinetics, 030220 oncology & carcinogenesis, Molecular Medicine, Immunology and Allergy, Medicine, In patient, Programmed death 1, business, 030304 developmental biology
Published
2016
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25. Early Carcinogenesis Involves the Establishment of Immune Privilege via Intrinsic and Extrinsic Regulation of Indoleamine 2,3-dioxygenase-1: Translational Implications in Cancer Immunotherapy

Author

Kathy Evans, Alisha Holtzhausen, Fei Zhao, and Brent A. Hanks

Subjects
lcsh:Immunologic diseases. Allergy, type III TGF-β receptor, beta-Catenin, indoleamine 2,3-dioxygenase, medicine.medical_treatment, Immunology, Review Article, Biology, medicine.disease_cause, Immune tolerance, tumor immunotherapy, tumor immune evasion, Immune system, Immune privilege, Cancer immunotherapy, medicine, Tumor Microenvironment, Immunology and Allergy, dendritic cells, Indoleamine 2,3-dioxygenase, Tumor microenvironment, Dendritic cell, β-catenin, Wnt5a, COX-2, Cancer research, Carcinogenesis, lcsh:RC581-607
Abstract

Although prolonged genetic pressure has been conjectured to be necessary for the eventual development of tumor immune evasion mechanisms, recent work is demonstrating that early genetic mutations are capable of moonlighting as both intrinsic and extrinsic modulators of the tumor immune microenvironment. The indoleamine 2,3-dioxygenase-1 (IDO) immunoregulatory enzyme is emerging as a key player in tumor-mediated immune tolerance. While loss of the tumor suppressor, BIN-1, and the over-expression of cyclooxygenase-2 (COX-2) have been implicated in intrinsic regulation of IDO, recent findings have demonstrated the loss of TβRIII and the upregulation of Wnt5a by developing cancers to play a role in the extrinsic control of IDO activity by local dendritic cell populations residing within tumor and tumor-draining lymph node tissues. Together, these genetic changes are capable of modulating paracrine signaling pathways in the early stages of carcinogenesis to establish a site of immune privilege by promoting the differentiation and activation of local regulatory T cells. Additional investigation of these immune evasion pathways promises to provide opportunities for the development of novel strategies to synergistically enhance the efficacy of the evolving class of T cell-targeted ‘checkpoint’ inhibitors.

Published
2014
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26. Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment

Author

Mark D. Starr, Olivia M. Campbell, Takayu Osada, Melissa Hector-Greene, Alisha Holtzhausen, Christi Augustine, Michael A. Morse, Petra Gimpel, Gerard C. Blobe, Georgia M. Beasley, Kathy Evans, Andrew B. Nixon, Douglas S. Tyler, Alok K. Tewari, Leona E. Ling, H. Kim Lyerly, Amanda George, Lihong Sun, Brent A. Hanks, and Rebekah Jamieson

Subjects
Chemokine, medicine.medical_treatment, Melanoma, Experimental, Down-Regulation, Mice, Transgenic, Mice, Immune system, Transforming Growth Factor beta, Cell Line, Tumor, medicine, Tumor Microenvironment, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Chemokine CCL22, Tumor microenvironment, Mice, Inbred BALB C, biology, Melanoma, Mammary Neoplasms, Experimental, General Medicine, Transforming growth factor beta, Immunotherapy, Dendritic Cells, medicine.disease, Mice, Inbred C57BL, Tumor Escape, Immunology, Cancer research, biology.protein, Female, Proteoglycans, Receptors, Transforming Growth Factor beta, CCL22, Neoplasm Transplantation, Research Article
Abstract

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.

Published
2013

27. Targeting the Wnt5a-β-catenin pathway in the melanoma microenvironment to augment checkpoint inhibitor immunotherapy

Author

Alisha Holtzhausen, Douglas S. Tyler, Fei Zhao, Masahito Tsutsui, Kathy Evans, and Brent A. Hanks

Subjects
Cancer Research, business.industry, medicine.medical_treatment, Immune checkpoint inhibitors, Melanoma, Immunotherapy, medicine.disease, WNT5A, Oncology, Catenin, medicine, Cancer research, In patient, Augment, business, Advanced melanoma
Abstract

3054 Background: While checkpoint inhibitor immunotherapy has demonstrated recent success in patients with advanced melanoma, a significant fraction of these patients continue to fail therapy. The ...

Published
2015
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28. Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma

Author

Alisha Holtzhausen, Michelle Heid, Kathy Evans, Brent A. Hanks, and Gerard C. Blobe

Subjects
Cancer Research, Tumor microenvironment, biology, business.industry, medicine.drug_class, Melanoma, medicine.medical_treatment, Dendritic cell, Immunotherapy, medicine.disease, Monoclonal antibody, Immune system, Oncology, Immunology, biology.protein, medicine, PTEN, Antibody, business
Abstract

3011 Background: T cell-targeted checkpoint inhibitor immunotherapy for melanoma and other solid tumor malignancies only benefits a subpopulation of patients. Our work has shown that melanoma-expressed factors including TGF-β can generate an immune privileged site by suppressing the function of critical dendritic cell populations within the local immune microenvironment. We hypothesized that inhibiting TGF-β signaling in the tumor microenvironment could augment the efficacy of anti-CTLA-4 antibody therapy in a murine transgenic model of melanoma. Methods: Upon primary melanoma development in Tyr::CreER;BrafCA/+;PTENlox/loxmice, the LY2157299 type I TGF-β receptor serine/threonine kinase inhibitor was administered daily by oral gavage accompanied by intra-peritoneal delivery of anti-CTLA-4 monoclonal antibody (mAb) every three days. Tumor development was monitored by caliper and photodocumentation/imaging analysis. After 14 days, tumor tissue, tumor-draining lymph node (TDLN) tissue, and lung tissue was re...

Published
2014
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29. Melanoma-derived Wnt5a conditions dendritic cells to promote regulatory T cell differentiation via the upregulation of indoleamine 2,3-dioxygenase: novel pharmacological strategies for augmenting immunotherapy efficacy

Author

Ciriana Orabona, Alisha Holtzhausen, Kathy Evans, Brent A. Hanks, and Fei Zhao

Subjects
Pharmacology, Cancer Research, Regulatory T cell differentiation, business.industry, Regulatory T cell, Immunology, Wnt signaling pathway, FOXP3, chemical and pharmacologic phenomena, Immune tolerance, PORCN, body regions, Paracrine signalling, medicine.anatomical_structure, Oncology, Poster Presentation, embryonic structures, Cancer research, Molecular Medicine, Immunology and Allergy, Medicine, business, Indoleamine 2,3-dioxygenase
Abstract

Previous studies have shown the β-catenin signaling pathway to promote the development of tolerogenic dendritic cells (DCs) that are capable of driving regulatory T cell (Treg) differentiation. Interestingly, tolerogenic DCs have recently been described to play a role in carcinogenesis. However, the molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are unknown. Using a genetically engineered model, we demonstrate that melanoma-derived Wnt5a ligand is a novel regulator of indoleamine 2,3-dioxygenase-1 (IDO) expression in local myeloid DCs and that Wnt5a induces the durable expression and enzymatic activity of IDO via β-catenin (Figures ​(Figures11,​,2).2). Further, we show that Wnt5a-conditioned DCs promote Treg differentiation in an IDO-dependent manner and that melanoma secretion of Wnt5a both suppresses the generation of anti-tumor immunity and promotes melanoma progression in vivo (Figure ​(Figure3).3). By genetically silencing the PORCN acyl transferase which is necessary for Wnt ligand secretion, we confirm the role of the soluble Wnt ligands in directing DC tolerization both in vitro and in vivo while also establishing a potential pharmacologic target for manipulating this novel pathway (Figure ​(Figure4).4). Indeed, utilizing a small molecule inhibitor of PORCN, we are able to reverse Wnt5a-mediated IDO upregulation by DCs both in vitro and in vivo. These findings were expanded in further melanoma studies where we demonstrated small molecule PORCN inhibition to synergistically suppress melanoma progression while also enhancing anti-melanoma immunity in the setting of combination anti-CTLA-4 therapy (Figure ​(Figure5).5). Additional work in human melanoma confirms the existence of this Wnt5a-mediated paracrine signaling pathway in DCs and reveals by microarray dataset analysis that human melanoma co-expression of Wnt5a and FoxP3 is highly significant. These data prompted us to hypothesize that a Wnt5a-induced gene signature in the melanoma microenvironment may be indicative of immune tolerance. Indeed, we have found that a Wnt5a gene signature identified in purified sentinel lymph node-derived DCs is associated with an inferior clinical prognosis in melanoma patients. This work emphasizes the importance of DC populations in directing tumor immune surveillance and illustrates that the molecular mechanisms involved in DC physiology represent potential targets for pharmacologically enhancing anti-tumor immunity. Figure 1 Wnt3a and Wnt5a upregulate IDO expression and activity in DCs. A. Wnt5a induces durable IDO expression by BMDCs based on Western blot analysis at 24 and 48 hrs. Representative of 3 independent experiments. UT, untreated. XAV939, β-catenin inhibitor. ... Figure 2 Murine melanomas induce paracrine β-catenin signaling activation in tumor and TDLN DCs in vivo. A.Tumor-infiltrating DCs (TIDCs) isolated from Tyr::CreER;BrafCA;Ptenlox/lox primary melanomas exhibit increased expression levels of β-catenin ... Figure 3 Wnt5a conditions DCs to drive regulatory T-cell cifferentiation. A. Schematic of in vitro Treg assay. B. Wnt5a-conditioned DCs stimulate CD4+FoxP3+ Treg differentiation in vitro following co-incubation with total splenic CD4+ T cells at a 1:1, 5:1 or ... Figure 4 Silencing PORCN expression in the B16 melanoma model enhances anti-tumor immunity and suppresses tumor progression in vivo. A. Silencing PORCN expression by B16/F10 cells suppresses paracrine β-catenin activation in a 293T-TCF/LEF1-luciferase ... Figure 5 C59 Inhibition of the Wnt-β-catenin signaling pathway synergistically enhances the efficacy of anti-CTLA-4 antibody immunotherapy in the B16 melanoma model. A. Combination inhibition of Wnt-mediated signaling and anti-CTLA-4 blockade synergistically ...

Published
2014
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30. Role of the Wnt-β-catenin signaling pathway in melanoma-mediated dendritic cell tolerization

Author

Kathy Evans, Brent A. Hanks, and Alisha Holtzhausen

Subjects
Pharmacology, Cancer Research, Tumor microenvironment, Regulatory T cell, business.industry, T cell, Immunology, Wnt signaling pathway, Dendritic cell, Immune tolerance, Cell biology, Paracrine signalling, medicine.anatomical_structure, Oncology, Poster Presentation, medicine, Molecular Medicine, Immunology and Allergy, Signal transduction, business
Abstract

Recent studies have shown that tumor immune evasion mechanisms significantly contribute to immunotherapy failure. Emerging data is indicating that tumor-associated dendritic cells (DCs) undergo phenotypic tolerization and promote the differentiation and activation of regulatory T cell (Treg) populations to generate local immune subversion. The critical role of DCs in orchestrating anti-tumor immunity suggests that the signaling pathways that regulate DC tolerogenesis may be promising targets for pharmacologically augmenting immunotherapy efficacy. Previous work has shown that the β-catenin signaling pathway plays a potential role in the DC tolerization process. Others have demonstrated that the DC-expressed enzyme, indoleamine 2,3-dioxygenase (IDO), promotes tumor-induced immune tolerance by catalyzing the conversion of the amino acid tryptophan into kynurenine. Other investigators have demonstrated melanomas to upregulate the expression of several Wnt ligands during their malignant transformation. Using a transgenic murine model of melanoma, we have determined that melanoma-associated DCs exhibit elevated levels of expression of IDO and other β-catenin target genes and demonstrate diminished T cell stimulatory capacity in vitro. Further studies have shown that Wnt3a and Wnt5a induce the expression and enzymatic activity of IDO in myeloid DCs (mDCs) in a β-catenin-dependent fashion while IDO reporter assays suggest this process to be mediated by direct promoter activation. This data suggest the Wnt-β-catenin signaling pathway to be a potential target for suppressing melanoma-induced DC tolerization and enhancing anti-tumor immunity. Indeed, both small molecule inhibition and genetic silencing of the PORCN acyl transferase enzyme which is necessary for Wnt secretion, abrogated B16 melanoma paracrine induction of β-catenin signaling and IDO expression by local mDCs. Further studies have shown PORCN-silenced B16 melanomas to exhibit reduced tumorigenecity in vivo and that this effect correlated with decreased mDC IDO expression and reduced levels of local Tregs. We therefore hypothesize that melanoma-expressed Wnt ligands induce DC tolerogenesis and stimulate β-catenin-dependent IDO expression and subsequent Treg generation in the tumor microenvironment, resulting in the development of an immunotolerant state and ultimately allowing for disease progression. Further, we propose that the pharmacological inhibition of this pathway can reverse this mechanism of immune evasion and enhance other immunotherapeutic approaches. Future work will include testing the ability of the small molecule PORCN inhibitor to stimulate the generation of tumor antigen-specific T cell responses in an autochthonous transgenic melanoma model.

Published
2013

31. Effect of the loss of the type III TGFβ receptor during tumor progression on tumor microenvironment: Preclinical development of TGFβ inhibition and TGFβ-related biomarkers to enhance immunotherapy efficacy

Author

Gerard C. Blobe, H. Kim Lyerly, Michael A. Morse, Alisha Holtzhausen, Olivia M. Campbell, Takuya Osada, Leona E. Ling, Douglas S. Tyler, Lihong Sun, Brent A. Hanks, Rebekah Jamieson, Petra Gimpel, and Christina K. Augustine

Subjects
Cancer Research, Tumor microenvironment, Oncology, Tumor progression, business.industry, Immune microenvironment, medicine.medical_treatment, Cancer research, medicine, Immunotherapy, Clinical efficacy, Receptor, business
Abstract

10563 Background: Overall, the clinical efficacy of tumor immunotherapy has been limited. Our incomplete understanding of the complex interplay between tumors and the immune microenvironment has contributed to these modest outcomes. Our work has revealed that several tumors downregulate the expression of the type III TGFβ receptor (TβRIII) with progression. TβRIII is shed from the cell surface to generate soluble TβRIII (sTβRIII) which is capable of sequestering TGFβ. Methods and Results: Using both breast cancer and melanoma tumor models we have demonstrated that the loss of TβRIII expression is associated with diminished tumor infiltrating CD8+ T cells and increased regulatory T cells (Tregs) within the tumor microenvironment. Our data implies that these alterations correlate with suppressed tumor antigen-specific T cell responses and more rapid disease progression. We show that these changes are due to enhanced TGFβ signaling within the immune compartment of the tumor microenvironment resulting in enhanced expression of the indoleamine 2,3-dioxygenase immunoregulatory enzyme by local plasmacytoid dendritic cells (DCs) as well as increased expression of the Treg-recruiting CCL22 chemokine by local myeloid DCs. Microarray analysis indicates that these same gene expression associations also exist in human breast cancers. Consistent with these studies, we have demonstrated that TGF-β inhibition synergistically enhances the efficacy of a Her2/neu vaccine in a breast cancer model and that plasma levels of sTβRIII correlate with clinical response and overall survival in stage III melanoma patients. Conclusions: We have elucidated a novel mechanism that tumors utilize to suppress the generation of anti-tumor immunity by establishing a link between the loss of an endogenous suppressor of tumor metastasis, TβRIII, and the generation of an immunotolerant tumor microenvironment. We are pursuing a phase I clinical trial to investigate the efficacy of combining a TGF-β inhibitor with a tumor vaccine while also determining if sTβRIII may function as a predictive biomarker for this approach.

Published
2012
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32. Abstract 3548: Loss of the type III TGF-β receptor during cancer progression generates an immunotolerant tumor microenvironment: Translational implications for TGF-β inhibition and immunotherapy biomarker development

Author

Petra Gimpel, Michael A. Morse, Alisha Holtzhausen, Gerard C. Blobe, Herbert Kim Lyerly, Brent A. Hanks, Rebekah Jamieson, Leona E. Ling, and Olivia M. Campbell

Subjects
Cancer Research, Tumor microenvironment, Chemistry, medicine.medical_treatment, Cancer, Immunotherapy, Endoglin, medicine.disease, Tgf β receptors, Oncology, Immunology, Cancer research, medicine, Biomarker (medicine), Transforming growth factor
Abstract

We have demonstrated that the type III TGF-β receptor (TβRIII) functions to suppress cancer progression and is downregulated in several malignancies. Previous work has shown TβRIII to undergo ectodomain shedding (sTβRIII), enabling the sequestration of the soluble TGF-β ligand and the inhibition of the downstream TGF-β signaling pathway. The TGF-β cytokine is an immunosuppressive factor expressed by many tumor types to dampen the host immune response and thereby allow for tumor progression. Dendritic cells (DC) are critical antigen presenting cells involved in orchestrating antigen-specific immunity. We therefore propose that the downregulation of TβRIII during cancer development permits enhanced TGF-β signaling within local DC populations of the tumor microenvironment, allowing for evasion of the host immune response. Our data suggests that the tumor suppressor properties of TβRIII in the 4T1 murine breast cancer model are significantly diminished in immunosuppressed hosts. Indeed, loss of TβRIII allows for the progression of more immunogenic Her2/neu-expressing 4T1 tumors in vivo and suppresses Her2/neu-specific T cell responses. Importantly, the local delivery of a TGF-β antibody into 4T1-RIIIlo tumors phenocopies 4T1-RIIIhi tumors suggesting that this phenomenon is mediated by sTβRIII-dependent inhibition of soluble TGF-β in the tumor microenvironment. We have shown that 4T1-RIIIhi tumors as well as their draining lymph nodes (TDLNs) exhibit increased numbers of infiltrating CD8+ T cells, diminished FoxP3+ regulatory T cell infiltration, a TH1-polarized cytokine profile, and a mature DC phenotype relative to 4T1-RIIIlo tumors. In vitro studies have shown 4T1-RIII conditioned media to inhibit TGF-β signaling within DCs and to enhance their maturation. In addition, studies have revealed DC populations within 4T1-RIIIhi tumors to express reduced levels of the immunosuppressive indoleamine 2,3-dioxygenase (IDO) enzyme. Further work has demonstrated that plasmacytoid DCs (pDCs) within TDLNs upregulate IDO expression in response to TGF-β stimulation and that IDO expression is suppressed in the presence of TβRIII-expressing tumors. Indeed, we have found that melanoma patients with elevated sTβRIII plasma levels exhibit superior responses to treatment. We conclude that the loss of the TβRIII tumor suppressor during breast carcinogenesis results in enhanced paracrine TGF-β signaling within the pDC compartment of the tumor microenvironment. This work implies that TβRIII downregulation represents a novel mechanism for evading the host anti-tumor immune response. These findings further support the targeting of TGF-β as a strategy to enhance the efficacy of immunotherapeutic approaches for solid tumors and suggests that sTβRIII may represent a biomarker for immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3548. doi:1538-7445.AM2012-3548

Published
2012
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33. Abstract 3035: Bone morphogenetic proteins signal through Smad2 and Smad3 to regulate cell migration and proliferation

Author

Tam How, Bradley C. Gersh, Alisha Holtzhausen, and Gerard C. Blobe

Subjects
Cancer Research, animal structures, Cell migration, GDF5, Biology, Bone morphogenetic protein, Bone morphogenetic protein 2, Cell biology, Oncology, embryonic structures, Phosphorylation, Signal transduction, Transcription factor, Transforming growth factor
Abstract

The TGF-β superfamily consists of a large number of growth factors, including transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs) that regulate cellular proliferation, differentiation, invasion, migration and apoptosis. TGF-β activates the transcription factors Smad2/3, as well as Smad1/5/8, while BMP stimulation results in the activation of Smad1/5/8. Unexpectedly, we have demonstrated that BMP family members, including BMP2, 3, 4, 7, 9 and GDF5 can also induce Smad2/3 phosphorylation and downstream gene transcription in ovarian, pancreatic and breast cancer cell lines. BMP2-induced Smad2 phosphorylation can be attenuated by expression of dominant negative TβRII or shRNA-mediated knockdown of TβRII, while BMP2-induced Smad3 phosphorylation can be attenuated by expression of dominant negative BMPRII or shRNA-mediated knockdown of BMPRII, suggesting different mechanisms of BMP-mediated activation of Smad2 and Smad3. BMP2-induced Smad1, Smad2 and Smad3 phosphorylation increase cell invasion, migration and proliferation, respectively. BMP stimulated Smad2/3 phosphorylation suggests that BMP-mediated effects on cancer progression may be regulated, in part, through these novel signaling pathways. Current studies are focused on further elucidating the role of BMP-induced Smad2 and Smad3 phosphorylation on human cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3035. doi:1538-7445.AM2012-3035

Published
2012
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34. Abstract 3972: The role of the TGF-β type III receptor in colon carcinogenesis

Author

Catherine E. Gatza, Kellye C. Kirkbride, and Alisha Holtzhausen

Subjects
Cancer Research, Gene knockdown, Colorectal cancer, Cancer, Biology, medicine.disease, medicine.disease_cause, digestive system diseases, Oncology, Tumor progression, Apoptosis, Immunology, Cancer research, medicine, Anoikis, Carcinogenesis, Transforming growth factor
Abstract

The loss of the TGF-β type III receptor (TβRIII), a TGF-β superfamily co-receptor, correlates with disease progression in multiple cancer types, suggesting that TβRIII plays a role in regulating tumor progression. TGF-β superfamily signaling is frequently dysregulated in colon cancer but the specific role of TβRIII in colon carcinogenesis has not been examined. In contrast to other cancer types, TβRIII mRNA expression is not altered in colon cancer and there is not a significant change in TβRIII protein expression in tumors compared to normal colon tissue. HT29 colon cancer cells overexpressing TβRIII (HT29-RIII) exhibit an increase in proliferation in response to TGF-β and BMP2 stimulation compared to HT29-Neo cells. This increase in proliferation is mediated through the down-regulation of p21. In a soft agar assay HT29-RIII cells demonstrate increased colony formation in response to ligand treatment. Additionally, HT29-RIII cells are resistant to anoikis and 5FU-induced apoptosis. Colon cancer cells expressing TβRIII also exhibit increased migration potential and this increase in migration can be abrogated by knockdown of TβRIII expression. Furthermore, cells over-expressing TβRIII show alterations in E-cadherin and actin organization. Taken together, these data suggest that TβRIII may have a pro-tumorigenic role in colon cancer tumorigenesis as it mediates ligand stimulated proliferation, resistance to apoptosis and increased migration. Further work is currently underway to more fully elucidate the role of TβRIII in colon cancer progression in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3972.

Published
2010
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35. Type III TGF-β Receptor Enhances Colon Cancer Cell Migration and Anchorage-Independent Growth

Author

Alisha Holtzhausen, Gerard C. Blobe, Kellye C. Kirkbride, Michael L. Gatza, Catherine E. Gatza, Michael B. Datto, and Allyson. Morton

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Cancer Research, Colorectal cancer, Mice, Nude, SMAD, Biology, lcsh:RC254-282, 03 medical and health sciences, Mice, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, medicine, Gene silencing, Animals, Humans, 030304 developmental biology, Cell Proliferation, Regulation of gene expression, 0303 health sciences, Mice, Inbred BALB C, Cell growth, Gene Expression Profiling, Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Xenograft Model Antitumor Assays, Cell biology, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Proteoglycans, Signal transduction, HT29 Cells, Receptors, Transforming Growth Factor beta, Transforming growth factor, Signal Transduction, Research Article
Abstract

The type III TGF-β receptor (TβRIII or betagylcan) is a TGF-β superfamily coreceptor with emerging roles in regulating TGF-β superfamily signaling and cancer progression. Alterations in TGF-β superfamily signaling are common in colon cancer; however, the role of TβRIII has not been examined. Although TβRIII expression is frequently lost at the message and protein level in human cancers and suppresses cancer progression in these contexts, here we demonstrate that, in colon cancer, TβRIII messenger RNA expression is not significantly altered and TβRIII expression is more frequently increased at the protein level, suggesting a distinct role for TβRIII in colon cancer. Increasing TβRIII expression in colon cancer model systems enhanced ligand-mediated phosphorylation of p38 and the Smad proteins, while switching TGF-β and BMP-2 from inhibitors to stimulators of colon cancer cell proliferation, inhibiting ligand-induced p21 and p27 expression. In addition, increasing TβRIII expression increased ligand-stimulated anchorage-independent growth, a resistance to ligand- and chemotherapy-induced apoptosis, cell migration and modestly increased tumorigenicity in vivo. In a reciprocal manner, silencing endogenous TβRIII expression decreased colon cancer cell migration. These data support a model whereby TβRIII mediates TGF-β superfamily ligand-induced colon cancer progression and support a context-dependent role for TβRIII in regulating cancer progression.

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