7 results on '"Derek A. Wainwright"'
Search Results
2. Reshaping the tumor microenvironment with oncolytic viruses, positive regulation of the immune synapse, and blockade of the immunosuppressive oncometabolic circuitry
- Author
-
Teresa T Nguyen, Dong Ho Shin, Sagar Sohoni, Sanjay K Singh, Yisel Rivera-Molina, Hong Jiang, Xuejun Fan, Joy Gumin, Frederick F Lang, Christopher Alvarez-Breckenridge, Filipa Godoy-Vitorino, Lisha Zhu, W Jim Zheng, Lijie Zhai, Erik Ladomersky, Kristen L Lauing, Marta M Alonso, Derek A Wainwright, Candelaria Gomez-Manzano, and Juan Fueyo
- Subjects
Pharmacology ,Cancer Research ,Immunology ,Glioma ,CD8-Positive T-Lymphocytes ,Mice ,Oncolytic Viruses ,Oncology ,Synapses ,Tumor Microenvironment ,Molecular Medicine ,Immunology and Allergy ,Animals ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Kynurenine - Abstract
BackgroundOncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy.MethodsWe used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography–mass spectrometry. Aryl hydrocarbon receptor (AhR) activation was analyzed by examination of promoter activity. Therapeutic efficacy was assessed by tumor histopathology and survival in syngeneic murine models of gliomas, including Indoleamine 2,3-dioxygenase (IDO)-/- mice. Flow cytometry was used for immunophenotyping and quantification of cell populations. Immune activation was examined in co-cultures of immune and cancer cells. T-cell depletion was used to identify the role played by specific cell populations. Rechallenge experiments were performed to identify the development of anti-tumor memory.ResultsBulk RNA-seq analyses showed the activation of the immunosuppressive IDO-kynurenine-AhR circuitry in response to Delta-24-RGDOX infection of tumors. To overcome the effect of this pivotal pathway, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. The combination therapy increased the frequency of CD8+ T cells and decreased the rate of myeloid-derived suppressor cell and immunosupressive Treg tumor populations in animal models of solid tumors. Functional studies demonstrated that IDO-blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of the effectors and suppressors of the tumor immune landscape significantly prolonged the survival in animal models of orthotopic gliomas.ConclusionsOur data identified for the first time the in vivo role of IDO-dependent immunosuppressive pathways in the resistance of solid tumors to oncolytic adenoviruses. Specifically, the IDO-Kyn-AhR activity was responsible for the resurface of local immunosuppression and resistance to therapy, which was ablated through IDO inhibition. Our data indicate that combined molecular and immune therapy may improve outcomes in human gliomas and other cancers treated with virotherapy.
- Published
- 2022
3. Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy
- Author
-
Jinyu Zhang, Jennifer D. Wu, Pablo Larrocha, Derek A. Wainwright, Payal Dhar, and Bin Zhang
- Subjects
0301 basic medicine ,Cancer Research ,Combination therapy ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Immunology ,CD8-Positive T-Lymphocytes ,Ligands ,lcsh:RC254-282 ,NKG2D ,03 medical and health sciences ,0302 clinical medicine ,Co-stimulation ,PD1 blockade ,Cell Line, Tumor ,Neoplasms ,MHC class I ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Cancer ,Pharmacology ,biology ,Chemistry ,CD28 ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Blockade ,030104 developmental biology ,Soluble MHC I chain related molecule (sMIC) ,Oncology ,NK Cell Lectin-Like Receptor Subfamily K ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Molecular Medicine ,Research Article - Abstract
Background Insufficient co-stimulation accounts for a great deal of the suboptimal activation of cytotoxic CD8 T cells (CTLs) and presumably unsatisfactory clinical expectation of PD1/PD-L1 therapy. Tumor-derived soluble NKG2D ligands are associated with poor clinical response to PD1/PD-L1 blockade therapy in cancer patients. One of the mostly occurring tumor-derived soluble NKG2D ligands, the soluble MHC I chain related molecule (sMIC) can impair co-stimulation to CD8 T cells. We investigated whether co-targeting sMIC can provide optimal co-stimulation to CTLs and enhance the therapeutic effect of PD1/PD-L1 blockades. Methods Single agent therapy of a PD1/PD-L1 blockade antibody or a sMIC-targeting non-blocking antibody or a combination therapy of the two antibodies were implied to well-characterized pre-clinical MIC/sMIC+ tumor models that closely resemble the NKG2D-mediated oncoimmune dynamics of MIC+ cancer patients. Therapeutic efficacy and associated effector mechanisms were evaluated. Results We show that antibody co-targeting sMIC enables or enhances the response of sMIC+ tumors to PD1/PD-L1 blockade therapy. The therapy response of the combination therapy was associated with enhanced antigen-specific CD8 T cell enrichment and function in tumors. We show that co-targeting sMIC with a nonblocking antibody provides antigen-specific CD8 T cells with NKG2D and CD28 dual co-stimulation, in addition to elimination of inhibitory signals, and thus amplifies antigen-specific CD8 T cell anti-tumor responses. Conclusion Our findings provide the proof-of-concept rationale and previously undiscovered mechanisms for co-targeting sMIC to enable and enhance the response to PD1/PD-L1 blockade therapy in sMIC+ cancer patients. Electronic supplementary material The online version of this article (10.1186/s40425-019-0693-y) contains supplementary material, which is available to authorized users.
- Published
- 2019
4. Workshop on challenges, insights, and future directions for mouse and humanized models in cancer immunology and immunotherapy: a report from the associated programs of the 2016 annual meeting for the Society for Immunotherapy of cancer
- Author
-
Elizabeth M. Jaffee, Derek A. Wainwright, Mario Sznol, A. Karolina Palucka, Andrew Zloza, Lisa M. Coussens, Philip Gotwals, Kwok-Kin Wong, Marcus Bosenberg, Arlene H. Sharpe, Amanda W. Lund, and Mark B. Headley
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Mouse-in-mouse ,medicine.medical_treatment ,Immunology ,Cancer immunotherapy ,Meeting Report ,Humanized mouse ,Mouse models ,lcsh:RC254-282 ,03 medical and health sciences ,medicine ,Immunology and Allergy ,Medical physics ,Cancer immunology ,Panel discussion ,Pharmacology ,business.industry ,Cancer ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Predictive value ,030104 developmental biology ,Tumor microenvironment ,Oncology ,Drug development ,Molecular Medicine ,Immunocompetent ,business - Abstract
Understanding how murine models can elucidate the mechanisms underlying antitumor immune responses and advance immune-based drug development is essential to advancing the field of cancer immunotherapy. The Society for Immunotherapy of Cancer (SITC) convened a workshop titled, “Challenges, Insights, and Future Directions for Mouse and Humanized Models in Cancer Immunology and Immunotherapy” as part of the SITC 31st Annual Meeting and Associated Programs on November 10, 2016 in National Harbor, MD. The workshop focused on key issues in optimizing models for cancer immunotherapy research, with discussions on the strengths and weaknesses of current models, approaches to improve the predictive value of mouse models, and advances in cancer modeling that are anticipated in the near future. This full-day program provided an introduction to the most common immunocompetent and humanized models used in cancer immunology and immunotherapy research, and addressed the use of models to evaluate immune-targeting therapies. Here, we summarize the workshop presentations and subsequent panel discussion.
- Published
- 2017
5. Glioma microenvironment-derived CCL2 recruits regulatory T cells and myeloid-derived suppressor cells
- Author
-
Yu Han, Mahua Dey, Derek A. Wainwright, Maciej S. Lesniak, Alan L. Chang, Lingjiao Zhang, Jian Qiao, Irina V. Balyasnikova, Jason Miska, Atique U. Ahmed, and Peter Pytel
- Subjects
Pharmacology ,Cancer Research ,CCR2 ,Chemokine ,biology ,Microglia ,business.industry ,medicine.medical_treatment ,Immunology ,CCL2 ,medicine.disease ,CCL20 ,Cytokine ,medicine.anatomical_structure ,Oncology ,Glioma ,Poster Presentation ,medicine ,biology.protein ,Myeloid-derived Suppressor Cell ,Molecular Medicine ,Immunology and Allergy ,business - Abstract
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults with a median survival of 14.6 months despite surgery, radiotherapy, and chemotherapy. One hallmark of GBM is the accumulation of potently immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). However, the factors underlying Treg and MDSC trafficking to GBM have not been well established. We identified C-C motif chemokine 2 (CCL2) as a glioma microenvironment-derived chemokine that recruits Tregs and MDSCs that express the cognate receptors CCR4 and CCR2, respectively. First, we found that CCL2 expression is a prognostic factor for GBM patients using data from The Cancer Genome Atlas. High CCL2 expression was correlated with a poor prognosis in both univariate and multivariate Cox regression analyses. We also confirmed the presence of CCL2 in GBM patient samples by immunohistochemical staining. In the syngeneic murine GL261 model of GBM, the major source of CCL2 was macrophages and microglia in the glioma microenvironment rather than tumor cells themselves. Treatment of ex vivo isolated microglia and bone marrow (BM)-derived macrophages with GL261 conditioned media resulted in CCL2 production, suggesting that a soluble GL261-derived factor was responsible for the production of CCL2 in microglia and macrophages. To identify potential candidates for this GL261-derived factor, a cytokine array was performed. We found that CCL20 was highly produced by the tumors and was sufficient for the stimulation of CCL2 production by BM-derived macrophages. Implantation of GL261 cells in Ccl2-/- mice resulted in reduced levels of Tregs and Ly-6C+ monocytic MDSCs but not Ly-6G+ granulocytic MDSCs. Finally, treatment of mice bearing intracranial GL261 tumors with the small molecule chemokine receptor antagonist C 021 increased median survival ~30%. Thus, the CCL2 chemokine-receptor axis is a potential therapeutic target in GBM as a major mechanism for the recruitment of Tregs and MDSCs.
- Published
- 2015
6. NKG2C/KLRC2 tumor cell expression enhances immunotherapeutic efficacy against glioblastoma
- Author
-
Derek A Wainwright, Aurelio Hernández-Laín, Maria E Rodriguez-Ruiz, Olaya de Dios, Carlos E De Andrea, Angel Pérez-Nuñez, Diego Megías, M Angeles Ramírez-González, Irene Gómez-Soria, Berta Segura-Collar, Juliana Manosalva, Leticia Fernández-Rubio, Juan M Sepúlveda-Sánchez, Ricardo Gargini, and Pilar Sánchez-Gómez
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Activating and inhibitory receptors of natural killer (NK) cells such as NKp, NKG2, or CLEC are highly relevant to cold tumors including glioblastoma (GBM). Here, we aimed to characterize the expression of these receptors in GBM to gain insight into their potential role as modulators of the intratumoral microenvironment.Methods We performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded by KLRC2, NKG2C, among bulk and single-cell RNA sequencing GBM data sets. We also evaluated the effects of KLRC2-overexpressing GL261 cells in mice treated with or without programmed cell death protein-1 (PD-1) monoclonal antibody (mAb). Finally, we analyzed samples from two clinical trials evaluating PD-1 mAb effects in patients with GBM to determine the potential of NKG2C to serve as a biomarker of response.Results We observed significant expression of several inhibitory NK receptors on GBM-infiltrating NK and T cells, which contrasts with the strong expression of KLRC2 on tumor cells, mainly at the infiltrative margin. Neoplastic KLRC2 expression was associated with a reduction in the number of myeloid-derived suppressor cells and with a higher level of tumor-resident lymphocytes. A stronger antitumor activity after PD-1 mAb treatment was observed in NKG2Chigh-expressing tumors both in mouse models and patients with GBM whereas the expression of inhibitory NK receptors showed an inverse association.Conclusions This study explored the role of neoplastic NKG2C/KLRC2 expression in shaping the immune profile of GBM and suggests that it is a predictive biomarker for positive responses to immune checkpoint inhibitor treatment in patients with GBM. Future studies could further validate this finding in prospective trials.
- Published
- 2024
- Full Text
- View/download PDF
7. Reshaping the tumor microenvironment with oncolytic viruses, positive regulation of the immune synapse, and blockade of the immunosuppressive oncometabolic circuitry
- Author
-
Filipa Godoy-Vitorino, Hong Jiang, W Jim Zheng, Frederick F Lang, Joy Gumin, Lisha Zhu, Candelaria Gomez-Manzano, Juan Fueyo, Derek A Wainwright, Dong Ho Shin, Teresa T Nguyen, Sagar Sohoni, Sanjay K Singh, Yisel Rivera-Molina, Xuejun Fan, Christopher Alvarez-Breckenridge, Lijie Zhai, Erik Ladomersky, Kristen L Lauing, and Marta M Alonso
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy.Methods We used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography–mass spectrometry. Aryl hydrocarbon receptor (AhR) activation was analyzed by examination of promoter activity. Therapeutic efficacy was assessed by tumor histopathology and survival in syngeneic murine models of gliomas, including Indoleamine 2,3-dioxygenase (IDO)-/- mice. Flow cytometry was used for immunophenotyping and quantification of cell populations. Immune activation was examined in co-cultures of immune and cancer cells. T-cell depletion was used to identify the role played by specific cell populations. Rechallenge experiments were performed to identify the development of anti-tumor memory.Results Bulk RNA-seq analyses showed the activation of the immunosuppressive IDO-kynurenine-AhR circuitry in response to Delta-24-RGDOX infection of tumors. To overcome the effect of this pivotal pathway, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. The combination therapy increased the frequency of CD8+ T cells and decreased the rate of myeloid-derived suppressor cell and immunosupressive Treg tumor populations in animal models of solid tumors. Functional studies demonstrated that IDO-blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of the effectors and suppressors of the tumor immune landscape significantly prolonged the survival in animal models of orthotopic gliomas.Conclusions Our data identified for the first time the in vivo role of IDO-dependent immunosuppressive pathways in the resistance of solid tumors to oncolytic adenoviruses. Specifically, the IDO-Kyn-AhR activity was responsible for the resurface of local immunosuppression and resistance to therapy, which was ablated through IDO inhibition. Our data indicate that combined molecular and immune therapy may improve outcomes in human gliomas and other cancers treated with virotherapy.
- Published
- 2022
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.