20 results on '"Pushpa Jayaraman"'
Search Results
2. SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
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Ye Wang, Morvarid Mohseni, Angelo Grauel, Javier Estrada Diez, Wei Guan, Simon Liang, Jiyoung Elizabeth Choi, Minying Pu, Dongshu Chen, Tyler Laszewski, Stephanie Schwartz, Jane Gu, Leandra Mansur, Tyler Burks, Lauren Brodeur, Roberto Velazquez, Steve Kovats, Bhavesh Pant, Giri Buruzula, Emily Deng, Julie T. Chen, Farid Sari-Sarraf, Christina Dornelas, Malini Varadarajan, Haiyan Yu, Chen Liu, Joanne Lim, Huai-Xiang Hao, Xiaomo Jiang, Anthony Malamas, Matthew J. LaMarche, Felipe Correa Geyer, Margaret McLaughlin, Carlotta Costa, Joel Wagner, David Ruddy, Pushpa Jayaraman, Nathaniel D. Kirkpatrick, Pu Zhang, Oleg Iartchouk, Kimberly Aardalen, Viviana Cremasco, Glenn Dranoff, Jeffrey A. Engelman, Serena Silver, Hongyun Wang, William D. Hastings, and Silvia Goldoni
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Medicine ,Science - Abstract
Abstract SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.
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- 2021
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3. TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts
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Angelo L. Grauel, Beverly Nguyen, David Ruddy, Tyler Laszewski, Stephanie Schwartz, Jonathan Chang, Julie Chen, Michelle Piquet, Marc Pelletier, Zheng Yan, Nathaniel D. Kirkpatrick, Jincheng Wu, Antoine deWeck, Markus Riester, Matt Hims, Felipe Correa Geyer, Joel Wagner, Kenzie MacIsaac, James Deeds, Rohan Diwanji, Pushpa Jayaraman, Yenyen Yu, Quincey Simmons, Shaobu Weng, Alina Raza, Brian Minie, Mirek Dostalek, Pavitra Chikkegowda, Vera Ruda, Oleg Iartchouk, Naiyan Chen, Raphael Thierry, Joseph Zhou, Iulian Pruteanu-Malinici, Claire Fabre, Jeffrey A. Engelman, Glenn Dranoff, and Viviana Cremasco
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Science - Abstract
Understanding the tumor microenviroment is important before it can be exploited therapeutically. Here, the authors use single cell sequencing to study stromal cells in mouse tumors and identify a subset of interferon-licensed cancer associated fibroblasts that appear after anti-TGFβ treatment.
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- 2020
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4. TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection.
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Pushpa Jayaraman, Miye K Jacques, Chen Zhu, Katherine M Steblenko, Britni L Stowell, Asaf Madi, Ana C Anderson, Vijay K Kuchroo, and Samuel M Behar
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain-containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF but more IL-10, and are functionally exhausted. Finally, we show that TIM3 blockade restores T cell function and improves bacterial control, particularly in chronically infected susceptible mice. These data show that T cell immunity is suboptimal during chronic M. tuberculosis infection due to T cell exhaustion. Moreover, in chronically infected mice, treatment with anti-TIM3 mAb is an effective therapeutic strategy against tuberculosis.
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- 2016
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5. Targeting the IL1β Pathway for Cancer Immunotherapy Remodels the Tumor Microenvironment and Enhances Antitumor Immune Responses
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Rohan Diwanji, Neil A. O'Brien, Jiyoung E. Choi, Beverly Nguyen, Tyler Laszewski, Angelo L. Grauel, Zheng Yan, Xin Xu, Jincheng Wu, David A. Ruddy, Michelle Piquet, Marc R. Pelletier, Alexander Savchenko, LaSalette Charette, Vanessa Rodrik-Outmezguine, Jason Baum, John M. Millholland, Connie C. Wong, Anne-Marie Martin, Glenn Dranoff, Iulian Pruteanu-Malinici, Viviana Cremasco, Catherine Sabatos-Peyton, and Pushpa Jayaraman
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Cancer Research ,Immunology - Abstract
High levels of IL1β can result in chronic inflammation, which in turn can promote tumor growth and metastasis. Inhibition of IL1β could therefore be a promising therapeutic option in the treatment of cancer. Here, the effects of IL1β blockade induced by the mAbs canakinumab and gevokizumab were evaluated alone or in combination with docetaxel, anti–programmed cell death protein 1 (anti–PD-1), anti-VEGFα, and anti-TGFβ treatment in syngeneic and humanized mouse models of cancers of different origin. Canakinumab and gevokizumab did not show notable efficacy as single-agent therapies; however, IL1β blockade enhanced the effectiveness of docetaxel and anti–PD-1. Accompanying these effects, blockade of IL1β alone or in combination induced significant remodeling of the tumor microenvironment (TME), with decreased numbers of immune suppressive cells and increased tumor infiltration by dendritic cells (DC) and effector T cells. Further investigation revealed that cancer-associated fibroblasts (CAF) were the cell type most affected by treatment with canakinumab or gevokizumab in terms of change in gene expression. IL1β inhibition drove phenotypic changes in CAF populations, particularly those with the ability to influence immune cell recruitment. These results suggest that the observed remodeling of the TME following IL1β blockade may stem from changes in CAF populations. Overall, the results presented here support the potential use of IL1β inhibition in cancer treatment. Further exploration in ongoing clinical studies will help identify the best combination partners for different cancer types, cancer stages, and lines of treatment.
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- 2023
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6. Supplementary Tables and Figures from Targeting the IL1β Pathway for Cancer Immunotherapy Remodels the Tumor Microenvironment and Enhances Antitumor Immune Responses
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Pushpa Jayaraman, Catherine Sabatos-Peyton, Viviana Cremasco, Iulian Pruteanu-Malinici, Glenn Dranoff, Anne-Marie Martin, Connie C. Wong, John M. Millholland, Jason Baum, Vanessa Rodrik-Outmezguine, LaSalette Charette, Alexander Savchenko, Marc R. Pelletier, Michelle Piquet, David A. Ruddy, Jincheng Wu, Xin Xu, Zheng Yan, Angelo L. Grauel, Tyler Laszewski, Beverly Nguyen, Jiyoung E. Choi, Neil A. O'Brien, and Rohan Diwanji
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Supplementary tables S1-S5 and figures S1-S7
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- 2023
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7. Data from Targeting the IL1β Pathway for Cancer Immunotherapy Remodels the Tumor Microenvironment and Enhances Antitumor Immune Responses
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Pushpa Jayaraman, Catherine Sabatos-Peyton, Viviana Cremasco, Iulian Pruteanu-Malinici, Glenn Dranoff, Anne-Marie Martin, Connie C. Wong, John M. Millholland, Jason Baum, Vanessa Rodrik-Outmezguine, LaSalette Charette, Alexander Savchenko, Marc R. Pelletier, Michelle Piquet, David A. Ruddy, Jincheng Wu, Xin Xu, Zheng Yan, Angelo L. Grauel, Tyler Laszewski, Beverly Nguyen, Jiyoung E. Choi, Neil A. O'Brien, and Rohan Diwanji
- Abstract
High levels of IL1β can result in chronic inflammation, which in turn can promote tumor growth and metastasis. Inhibition of IL1β could therefore be a promising therapeutic option in the treatment of cancer. Here, the effects of IL1β blockade induced by the mAbs canakinumab and gevokizumab were evaluated alone or in combination with docetaxel, anti–programmed cell death protein 1 (anti–PD-1), anti-VEGFα, and anti-TGFβ treatment in syngeneic and humanized mouse models of cancers of different origin. Canakinumab and gevokizumab did not show notable efficacy as single-agent therapies; however, IL1β blockade enhanced the effectiveness of docetaxel and anti–PD-1. Accompanying these effects, blockade of IL1β alone or in combination induced significant remodeling of the tumor microenvironment (TME), with decreased numbers of immune suppressive cells and increased tumor infiltration by dendritic cells (DC) and effector T cells. Further investigation revealed that cancer-associated fibroblasts (CAF) were the cell type most affected by treatment with canakinumab or gevokizumab in terms of change in gene expression. IL1β inhibition drove phenotypic changes in CAF populations, particularly those with the ability to influence immune cell recruitment. These results suggest that the observed remodeling of the TME following IL1β blockade may stem from changes in CAF populations. Overall, the results presented here support the potential use of IL1β inhibition in cancer treatment. Further exploration in ongoing clinical studies will help identify the best combination partners for different cancer types, cancer stages, and lines of treatment.
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- 2023
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8. Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment
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Hannah Egan, Oliver Treacy, Kevin Lynch, Niamh A. Leonard, Grace O’Malley, Eileen Reidy, Aoise O’Neill, Shania M. Corry, Kim De Veirman, Karin Vanderkerken, Laurence J. Egan, Thomas Ritter, Aisling M. Hogan, Keara Redmond, Li Peng, Jenny Che, Wayne Gatlin, Pushpa Jayaraman, Margaret Sheehan, Aoife Canney, Sean O. Hynes, Emma M. Kerr, Philip D. Dunne, Michael E. O’Dwyer, Aideen E. Ryan, Brussels Heritage Lab, Basic (bio-) Medical Sciences, Hematology, International Relations and Mobility, and R&D centraal
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T cell exhaustion ,hematology ,Immunology ,T cells ,CP: Immunology ,General Biochemistry, Genetics and Molecular Biology ,sialylation ,colon cancer ,inflammation ,oncology ,siglecs ,immunotherapy ,CP: Cancer ,cancer-associated fibroblasts ,TUMOR MICROENVIRONMENT ,stromal cells - Abstract
Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8+ PD1+ and CD8+ Siglec-7+/Siglec-9+ T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8+ T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.
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- 2023
9. 772 A phase 1/2 dose escalation/expansion study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of E-602, a bi-sialidase fusion protein, in advanced cancer (GLIMMER-01)
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Manish Sharma, Deanne Lathers, Melissa Johnson, Jason Luke, Igor Puzanov, Brendan Curti, Christopher Chen, Anthony El-Khoueiry, Brian Henick, Margaret Callahan, Mario Sznol, Sandip Patel, Dawn Wilson, Melissa Ricker, Lizhi Cao, Pushpa Jayaraman, Jenny Che, Li Peng, David Feltquate, and Anthony Tolcher
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- 2022
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10. TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts
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Zheng Yan, Raphael Thierry, Antoine deWeck, Claire Fabre, Felipe Correa Geyer, Joel Wagner, Oleg Iartchouk, Jeffrey A. Engelman, Beverly Nguyen, Rohan Diwanji, James Deeds, Julie Chen, Quincey Simmons, Naiyan Chen, Viviana Cremasco, Jonathan Chang, Joseph X. Zhou, Matt Hims, Yenyen Yu, Shaobu Weng, Pushpa Jayaraman, Stephanie Schwartz, David A. Ruddy, Michelle Piquet, Vera M. Ruda, Nathaniel D. Kirkpatrick, Pavitra Chikkegowda, Mirek Dostalek, Iulian Pruteanu-Malinici, Brian Minie, Glenn Dranoff, Markus Riester, Marc Pelletier, Alina Raza, Angelo Grauel, Kenzie MacIsaac, Jincheng Wu, and Tyler Laszewski
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0301 basic medicine ,Stromal cell ,medicine.medical_treatment ,Science ,Cell Plasticity ,Programmed Cell Death 1 Receptor ,Population ,General Physics and Astronomy ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cancer-Associated Fibroblasts ,Transforming Growth Factor beta ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Microenvironment ,medicine ,Animals ,Humans ,education ,Immune Checkpoint Inhibitors ,education.field_of_study ,Tumor microenvironment ,Multidisciplinary ,Carcinoma ,Mesenchymal stem cell ,Drug Synergism ,Interferon-beta ,General Chemistry ,Immunotherapy ,Disease Models, Animal ,030104 developmental biology ,Single cell sequencing ,030220 oncology & carcinogenesis ,Cancer research ,Tumour immunology ,Female ,Stromal Cells ,Myofibroblast - Abstract
Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy., Understanding the tumor microenviroment is important before it can be exploited therapeutically. Here, the authors use single cell sequencing to study stromal cells in mouse tumors and identify a subset of interferon-licensed cancer associated fibroblasts that appear after anti-TGFβ treatment.
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- 2020
11. Abstract CT034: GLIMMER-01: initial results from a phase 1 dose escalation trial of a first-in-class bi-sialidase (E-602) in solid tumors
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Jason J. Luke, Melissa Johnson, Anthony Tolcher, Christopher T. Chen, Tong Dai, Brendan D. Curti, Anthony El-Khoueiry, Mario Sznol, Brian S. Henick, Christine Horak, Pushpa Jayaraman, Christopher B. Cole, Dawn Wilson, Lizhi Cao, Li Peng, David Feltquate, Deanne Lathers, and Manish R. Sharma
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Cancer Research ,Oncology - Abstract
Background: Hypersialylation (excessive sialoglycans) on tumor cells has been known to be associated with poorer cancer outcomes for more than 40 years. Sialoglycans are immune suppressive and promote tumor immune evasion by binding to sialoglycan receptors (e.g. Siglecs) expressed on immune cells. However, redundant immune cell expression among Siglecs has posed a challenge for receptor-targeting therapeutic approaches. E-602 is a first-in-class fusion protein of engineered human sialidase (Neu2) and a human IgG1 Fc region. The dimeric sialidase moieties of E-602 circumvent the redundancy of this biology by directly cleaving terminal sialic acid residues from sialoglycans on immune and tumor cells. In preclinical studies, E-602 enhanced immune function by augmenting antigen-specific priming and activation of T cells and restoring function of exhausted-like T cells, and E-602 demonstrated antitumor activity as monotherapy in multiple mouse tumor models. Methods: A Phase 1/2 first-in-human dose escalation study is evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of E-602 in patients with advanced cancers. Eligible patients with select advanced solid tumors were treated with E-602 IV once weekly at dose levels between 1 and 30 mg/kg. Circulating immune cells were analyzed for changes in sialylation and immunophenotyping by flow cytometry. Changes in circulating cytokines were measured by immunoassays. Results: As of January 6, 2023, 32 patients were treated with at least one dose of E-602. The most common tumors treated were colorectal (n=18) and pancreatic (n=6). Doses up to 30 mg/kg were tolerated with no dose-limiting toxicities. The most frequent adverse event was infusion-related reactions which were primarily grade 1-2 and clinically manageable. PK was linear across the evaluated dose range with an estimated T1/2 of 9-24 hours. Dose dependent PD observations included (1) desialylation of peripheral CD8+ T, CD4+ T, and NK cells, remaining detectable in some patients at 7 days post-dose; (2) increases in the immune activation marker, CD69, on peripheral CD8+ T, CD4+ T, and NK cells; and (3) increases in the IFNγ-dependent chemokine CXCL10, TNF-α, and MIP1-β. Thus far, response-evaluable patients have had stable or progressive disease. Additional safety, PK, PD, and clinical outcomes for other patients treated as part of backfill at multiple dose levels will be reported at the meeting. Conclusion: E-602 is tolerated at doses up to 30 mg/kg. Consistent with preclinical findings, dose-dependent desialylation and immune system activation were observed. Based on the observed tolerability and PD effects, the Phase 2 portion of the study to evaluate clinical activity of E-602 monotherapy in patients with checkpoint-inhibitor resistant NSCLC and melanoma will proceed. Citation Format: Jason J. Luke, Melissa Johnson, Anthony Tolcher, Christopher T. Chen, Tong Dai, Brendan D. Curti, Anthony El-Khoueiry, Mario Sznol, Brian S. Henick, Christine Horak, Pushpa Jayaraman, Christopher B. Cole, Dawn Wilson, Lizhi Cao, Li Peng, David Feltquate, Deanne Lathers, Manish R. Sharma. GLIMMER-01: initial results from a phase 1 dose escalation trial of a first-in-class bi-sialidase (E-602) in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT034.
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- 2023
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12. Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor
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Stephanie Schwartz, Nidhi Patel, Tyler Longmire, Pushpa Jayaraman, Xiaomo Jiang, Hongbo Lu, Lisa Baker, Janelle Velez, Radha Ramesh, Anne-Sophie Wavreille, Melanie Verneret, Hong Fan, Tiancen Hu, Fangmin Xu, John Taraszka, Marc Pelletier, Joy Miyashiro, Mikael Rinne, Glenn Dranoff, Catherine Sabatos-Peyton, and Viviana Cremasco
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General Medicine - Abstract
Objectives Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab. Methods Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed. Results Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9. Conclusion Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.
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- 2022
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13. 439 Dual modes of action for anti-TIM-3 antibody MBG453 in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): preclinical evidence for immune-mediated and anti-leukemic activity
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Anne-Sophie Wavreille, Shumei Qiu, Viviana Cremasco, Glenn Dranoff, Xiaomo Jiang, Melanie Verneret, Mikael L. Rinne, Nidhi Patel, Hongbo Lu, Fiona Sharp, Catherine Anne Sabatos-Peyton, Pushpa Jayaraman, Stephanie Schwartz, Lisa Baker, and Tyler Longmire
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business.industry ,Myelodysplastic syndromes ,Azacitidine ,Myeloid leukemia ,Decitabine ,medicine.disease ,Stem cell marker ,Cell killing ,Hypomethylating agent ,Cancer research ,Medicine ,Stem cell ,business ,medicine.drug - Abstract
Background TIM-3 is expressed on leukemic stem cells (LSCs) and blasts in AML,1 2 and TIM-3 expression on MDS blasts correlates with disease progression.3 Functional evidence for TIM-3 in AML was established with an anti-TIM-3 antibody which inhibited engraftment and development of human AML in immuno-deficient murine hosts.1 TIM-3 promotes an autocrine stimulatory loop via the TIM-3/Galectin-9 interaction, supporting LSC self-renewal.4 In addition to its cell-autonomous role on LSCs/blasts, TIM-3 also has a critical role in immune system regulation, in adaptive (CD4+ and CD8+ T effector cells, regulatory T cells) and innate (macrophages, dendritic cells, NK cells) immune responses.5 MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 antibody (Ab) (stabilized hinge, S228P), which blocks the binding of TIM-3 to phosphatidylserine (PtdSer). Recent results from a multi-center, open label phase Ib dose-escalation study (NCT03066648) in patients with high-risk MDS and no prior hypomethylating agent therapy evaluating MBG453 in combination with decitabine demonstrated encouraging preliminary efficacy with an overall response rate of 58%,6 and MBG453 combined with azacitidine also showed encouraging response rates.7 Preclinical experiments were undertaken to define the mechanism of action of the hypomethylating agent and anti-TIM-3 combination. Methods THP-1 cells (a human monocytic AML cell line) were pre-treated with decitabine and co-cultured with anti-CD3 activated healthy human donor peripheral blood mononuclear cells (PBMCs) in an Incucyte-based assay to measure cell killing. The ability of MBG453 to mediate antibody-dependent cellular phagocytosis (ADCP) was measured by determining the phagocytic uptake of an engineered TIM-3-overexpressing Raji cell line in the presence of MBG453 by phorbol 12-myristate 13-acetate (PMA)-activated THP-1 cells. Patient-derived AML xenograft studies were undertaken in immune-deficient murine hosts to evaluate the combination of decitabine and MBG453. Results MBG453 was determined to partially block the TIM-3/Galectin-9 interaction in a plate-based MSD (Meso Scale Discovery) assay, supported by a crystal structure of human TIM-3.8 Pre-treatment of THP-1 cells with decitabine enhanced sensitivity to immune-mediated killing in the presence of MBG453. MBG453 was determined to mediate modest ADCP, relative to controls. MBG453 did not enhance the anti-leukemic activity of decitabine in patient-derived xenograft studies in immuno-deficient hosts. Conclusions Taken together, these results support both direct anti-leukemic effects and immune-mediated modulation by MBG453. Further studies are ongoing to determine: (1) whether MBG453 can mediate physiologically relevant ADCP of TIM-3-expressing leukemic cells; and (2) the potential of MBG453 to impact the autocrine feedback loop of TIM-3/Galectin-9. Ethics Approval The human tissue used in these studies was under the Novartis Institutes of BioMedical Research Ethics Board IRB, Approval Number 201252867. References Kikushige Y, Shima T, Takayanagi S, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 2010;7(6):708–717. Jan M, Chao MP, Cha AC, et al. Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci USA 2011; 108(12): 5009–5014. Asayama T, Tamura H, Ishibashi M, et al. Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes. Oncotarget 2017;8(51): 88904–88917. Kikushige Y, Miyamoto T, Yuda J, et al. A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell 2015; 17(3):341–352. Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer 2020; 8(1):e000911. Borate U, Esteve J, Porkka K, et al. Phase Ib Study of the Anti-TIM-3 Antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood 2019;134 (Supplement_1):570. Borate U, Esteve J, Porkka K, et al. Abstract S185: Anti-TIM-3 antibody MBG453 in combination with hypomethylating agents (HMAs) in patients (pts) with high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML): a Phase 1 study. EHA 2020. Sabatos-Peyton C. MBG453: A high affinity, ligand-blocking anti-TIM-3 monoclonal Ab. AACR 2016.
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- 2020
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14. Multiple Inflammatory Cytokines Converge To Regulate CD8+ T Cell Expansion and Function during Tuberculosis
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Stephen M. Carpenter, Cláudio Nunes-Alves, Matthew G. Booty, Pushpa Jayaraman, and Samuel M. Behar
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0301 basic medicine ,medicine.medical_treatment ,T cell ,Immunology ,Priming (immunology) ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Article ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,Interleukin 21 ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Tuberculosis, Pulmonary ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Cell Differentiation ,Flow Cytometry ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Cytokines ,Female ,Cytokine receptor ,CD8 ,030215 immunology - Abstract
The differentiation of effector CD8+ T cells is a dynamically regulated process that varies during different infections and is influenced by the inflammatory milieu of the host. In this study, we define three signals regulating CD8+ T cell responses during tuberculosis by focusing on cytokines known to affect disease outcome: IL-12, type I IFN, and IL-27. Using mixed bone marrow chimeras, we compared wild-type and cytokine receptor knockout CD8+ T cells within the same mouse following aerosol infection with Mycobacterium tuberculosis. Four weeks postinfection, IL-12, type 1 IFN, and IL-27 were all required for efficient CD8+ T cell expansion in the lungs. We next determined if these cytokines directly promote CD8+ T cell priming or are required only for expansion in the lungs. Using retrogenic CD8+ T cells specific for the M. tuberculosis Ag TB10.4 (EsxH), we observed that IL-12 is the dominant cytokine driving both CD8+ T cell priming in the lymph node and expansion in the lungs; however, type I IFN and IL-27 have nonredundant roles supporting pulmonary CD8+ T cell expansion. Thus, IL-12 is a major signal promoting priming in the lymph node, but a multitude of inflammatory signals converge in the lung to promote continued expansion. Furthermore, these cytokines regulate the differentiation and function of CD8+ T cells during tuberculosis. These data demonstrate distinct and overlapping roles for each of the cytokines examined and underscore the complexity of CD8+ T cell regulation during tuberculosis.
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- 2016
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15. Abstract 5640: Targeting tumor-promoting inflammation (TPI) via the IL-1βpathway for cancer immunotherapy
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Tong Luo, Anne-Marie Martin, Catherine Anne Sabatos-Peyton, Valerie Rezek, Alexander Savchenko, Marc Pelletier, Muchun Wang, Vanessa Rodrik-Outmezguine, Pushpa Jayaraman, John Millholland, Scott G. Kitchen, Rohan Diwanji, Wong Connie C, Jason Baum, Neil A. O'Brien, Kristine Rose, Glenn Dranoff, Elizabeth Choi, and Ronald Linnartz
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Cancer Research ,Tumor microenvironment ,Tumor-infiltrating lymphocytes ,business.industry ,medicine.medical_treatment ,Cancer ,Pembrolizumab ,Tumor initiation ,medicine.disease ,Oncology ,Cancer immunotherapy ,Humanized mouse ,Cancer research ,medicine ,business ,Lung cancer - Abstract
Introduction: TPI is a hallmark of cancer and plays a pivotal role in tumor initiation, development, progression, and invasiveness. High levels of tumor-promoting inflammatory cytokines e.g. IL-1β and IL-6 are associated with advanced malignancies and reduced survival. Selective IL-1β inhibitors like canakinumab (CAN) and gevokizumab (GEV) aim to target TPI within the tumor microenvironment (TME) by reducing tumor-associated immune suppression. In phase III CANTOS study, CAN significantly reduced lung cancer (LC) incidences and LC related mortalities in atherosclerosis patients, providing the first clinical evidence for the role of IL-1β inhibition in LC. We have utilized preclinical models to gain further insights into the mechanistic role of CAN and GEV in cancer development and progression. Methods: Preclinical efficacy of anti-human IL-1β antibodies, CAN and GEV was assessed using humanized mouse models of non-small cell lung cancer (NSCLC, H358), triple-negative breast cancer (TNBC, MDA-MB-231) and colorectal cancer (CRC, SW480) either as single agents or in combination with other immunomodulatory agents including PD-1 inhibitor pembrolizumab (PEM) and anti-VEGF therapy. A murine surrogate IL-1β blocking antibody clone 01BSUR was used to evaluate efficacy in murine syngeneic models of breast (4T1) and lung (LL-2) cancer either as single agent or with PD-1 inhibitor and docetaxel (DOC). Tumor infiltrating lymphocytes (TIL) characterization was carried out by flow cytometry and IHC in syngeneic and humanized models, respectively. Results: The IL-1β inhibitors showed anti-tumor activity in both murine syngeneic and humanized models as single agents or with other agents. In the H358 NSCLC mouse model, CAN + PEM significantly inhibited tumor growth and was associated with >50% regression vs control. Decreased tumor growth was also observed with GEV treatment in the SW480 CRC mouse model, both alone and with anti-VEGF therapy. In GEV+anti-VEGF arm, a decrease in tolerogenic DC-10 immune populations and an increase in CD45+ immune cells and CD68+ myeloid cells were also observed. In the MDA-MB-231 TNBC mouse model, CAN single-agent showed a decrease in tumor growth vs control. In murine syngeneic 4T1 and LL-2 models, anti-IL-1β alone and anti-IL-1β + anti-PD-1 resulted in increased presence of CD8+ T cells and reduction of immunosuppressive myeloid-derived suppressor cells, neutrophils, and regulatory T cells in the tumor, suggesting that the TME may be shifting to a less suppressive phenotype after IL-1β blockade. Similar changes were observed with combination of anti-IL-1β with DOC and anti-VEGF in murine syngeneic models. Conclusions: These data provide key insights into the biology behind IL-1β blockade currently being pursued in clinical trials with CAN and GEV. Additional preclinical studies to investigate mechanism of action of these agents and other novel combinations are planned. Citation Format: Pushpa Jayaraman, Vanessa Rodrik-Outmezguine, John Millholland, Neil O'Brien, Connie Wong, Rohan Diwanji, Muchun Wang, Elizabeth Choi, Ronald Linnartz, Kristine Rose, Marc Pelletier, Alexander Savchenko, Tong Luo, Valerie Rezek, Scott Kitchen, Jason Baum, Catherine Sabatos-Peyton, Anne-Marie Martin, Glenn Dranoff. Targeting tumor-promoting inflammation (TPI) via the IL-1βpathway for cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5640.
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- 2020
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16. Abstract A76: Anti IL-1b as a cancer immunotherapy
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Derek Y. Chiang, Catherine Anne Sabatos-Peyton, Rohan Diwanji, Glenn Dranoff, Reshma Singh, and Pushpa Jayaraman
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Cancer Research ,Tumor microenvironment ,business.industry ,medicine.medical_treatment ,Immunology ,Cancer ,Immunotherapy ,medicine.disease ,medicine.disease_cause ,Proinflammatory cytokine ,Cytokine ,Cancer immunotherapy ,Cancer research ,Medicine ,business ,Lung cancer ,Carcinogenesis - Abstract
Inflammation in cancer can both suppress tumor growth and promote tumorigenesis. In the tumor microenvironment (TME), inflammation characterized by inflammatory cells and other mediators including cytokines affects tumor development and progression and can have an impact on response to therapy. The inflammatory cytokine IL-1b is upregulated in several conditions including rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease, as well as in different cancers including breast, gastric, pancreatic, and lung cancers. IL-1b contributes to the generation and accumulation of myeloid-derived suppressor cells (MDSCs). In the tumor microenvironment, MDSCs consist of a mixture of immature macrophages, immature dendritic cells and neutrophils, which can suppress the function of antitumor T cells. In addition, IL-1b is produced via activation of the inflammasome, which has been shown to promote the infiltration of MDSCs and tumor-associated macrophages (TAMs) into the TME. Downstream of IL-1b production are other inflammatory cytokines such as IL-6, IL-8, and IL-17, which can also suppress the immune system. Recently published data show that blocking IL-1b in patients without cancer can lead to a decrease in fatal cancer and more specifically lung cancer incidences and fatalities (Ridker et al., 2017). While the study was not designed to study the anticancer effects of canakinumab (Ilaris), this finding has led to increased interest in understanding the role of IL-1b and IL-1b blockade in cancer development and progression. Emerging data aim to elucidate the role of IL-1b blockade on tumor growth and progression, as well as characterize changes to tumor-infiltrating lymphocyte (TIL) populations and their function after treatment with an anti-IL-1b antibody. Reference: Ridker PM et al. Effect of interleukin-1b inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomized, double-blind, placebo-controlled trial. Lancet 2017;390:1833-42. Citation Format: Reshma Singh, Rohan Diwanji, Pushpa Jayaraman, Derek Chiang, Catherine Sabatos-Peyton, Glenn Dranoff. Anti IL-1b as a cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A76.
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- 2020
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17. Abstract C103: Targeting IL-1β pathway for cancer immunotherapy
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Kristine Rose, Ronald Linnartz, Neil A. O'Brien, Vanessa Rodrik-Outmezguine, Marc Pelletier, Pushpa Jayaraman, John Millholland, Rohan Diwanji, Elizabeth Choi, Muchun Wang, Wong Connie C, Alexander Savchenko, Scott G. Kitchen, Jason Baum, Tong Luo, Catherine Anne Sabatos-Peyton, Anne-Marie Martin, Valerie Rezek, and Glenn Dranoff
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Cancer Research ,Tumor microenvironment ,Gevokizumab ,business.industry ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,Pembrolizumab ,medicine.disease ,Canakinumab ,Oncology ,Cancer immunotherapy ,Humanized mouse ,Cancer research ,Medicine ,business ,Lung cancer ,medicine.drug - Abstract
Introduction: Inflammation is a hallmark of cancer wherein diverse immune cells exert either pro- or antitumor properties and affect therapeutic resistance (Ritter B et al, JEM 2019). High concentrations of tumor-promoting inflammatory cytokines such as IL-1β (Litmanovich A et al, Oncol Ther 2018) and IL-6 (Altundag O et al, J Clin Oncol 2005) correlate with advanced malignancies and are associated with reduced survival. A recent phase III clinical trial (CANTOS) demonstrated that canakinumab, a selective IL-1β inhibitor, could significantly reduce lung cancer incidences and lung cancer related mortalities as a secondary endpoint in atherosclerosis patients, providing the first clinical evidence for the role of IL-1β inhibition in lung cancer. Canakinumab and other selective IL-1β inhibitors such as gevokizumab aim to target tumor promoting inflammation (TPI) within the tumor microenvironment (TME) by reducing tumor-associated immune suppression. In an effort to gain further insights into the clinical mechanistic role of canakinumab and gevokizumab in cancer development and progression, we have utilized preclinical models to understand the immunological events following IL-1β blockade. Methods: Preclinical efficacy of anti-human IL-1β antibodies, canakinumab and gevokizumab, was assessed in humanized mouse models of NSCLC (H358) and CRC (SW480) respectively. Anti-mouse IL-1β blocking antibody was used to evaluate efficacy in murine syngeneic models of breast (4T1) and lung (LL-2) cancer either as a single agent or in combination with PD-1 inhibitor and docetaxel. Tumor infiltrating lymphocytes (TIL) characterization was carried out either by flow cytometry or by IHC in syngeneic and humanized models. Results: Using both murine syngeneic and humanized mouse models, we demonstrate that IL-1β inhibition remodels the TME and slows tumor growth either alone or in combination with other agents. In the humanized H358 NSCLC mouse model, the combination of canakinumab and the anti-PD-1 monoclonal antibody, pembrolizumab, significantly slowed tumor growth by more than 50% vs control antibodies. Furthermore, canakinumab alone and in combination resulted in increased CD8 and CD3 positive TIL infiltration within the tumor. Decreased tumor growth was also observed with another IL-1β inhibitor, gevokizumab, in a humanized SW480 CRC mouse model, both alone and in combination with anti-VEGF therapy. In syngeneic 4T1 and LL-2 models, anti-IL-1β alone and in combination with anti-PD-1 resulted in increased infiltration of CD8+ cells along with the reduction of immunosuppressive myeloid derived suppressor cells (MDSCs), neutrophils and regulatory T cells (Tregs) into the tumor, suggesting that the TME may be shifting to a less suppressive phenotype after IL-1β blockade. Similar changes to the tumor microenvironment were observed with the combination of anti-IL-1β with docetaxel. Additional combinations are being explored in other tumor models reflecting different indications. Conclusions: Our results highlight the role for IL-1β in tumor immunomodulation and that the pathophysiological role of the IL-1β pathway in innate immunity might have important consequences on T cell function and checkpoint blockade in cancer. These results support the ongoing clinical evaluation of IL-1β inhibitors such as canakinumab and gevokizumab and in combination with other therapeutic agents across several cancers. Citation Format: Pushpa Jayaraman, John Millholland, Neil O’Brien, Connie Wong, Rohan Diwanji, Muchun Wang, Elizabeth Choi, Ronald Linnartz, Kristine Rose, Vanessa Rodrik-Outmezguine, Marc Pelletier, Alexander Savchenko, Tong Luo, Valerie Rezek, Scott Kitchen, Jason Baum, Catherine Sabatos-Peyton, Anne-Marie Martin, Glenn Dranoff . Targeting IL-1β pathway for cancer immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C103. doi:10.1158/1535-7163.TARG-19-C103
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- 2019
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18. IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection
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Gillian Beamer, Cláudio Nunes-Alves, Matthew G. Booty, Britni L. Stowell, Palmira Barreira-Silva, Samuel M. Behar, Pushpa Jayaraman, Stephen M. Carpenter, Miye K. Jacques, and Universidade do Minho
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0301 basic medicine ,CD4-Positive T-Lymphocytes ,T cell ,Programmed Cell Death 1 Receptor ,Medicina Básica [Ciências Médicas] ,Bone Marrow Cells ,Mice, Transgenic ,Biology ,CD8-Positive T-Lymphocytes ,Article ,03 medical and health sciences ,Interleukin 21 ,Interferon-gamma ,Mice ,0302 clinical medicine ,medicine ,Cytotoxic T cell ,Animals ,Tuberculosis ,IL-2 receptor ,Hepatitis A Virus Cellular Receptor 2 ,Lung ,Disease Resistance ,Mice, Knockout ,Multidisciplinary ,Science & Technology ,ZAP70 ,Interleukins ,CD28 ,Mycobacterium tuberculosis ,Natural killer T cell ,T cell cytokine production ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Ciências Médicas::Medicina Básica ,Cytokines ,Female ,Biomarkers ,030215 immunology ,Signal Transduction - Abstract
IL-21 is produced predominantly by activated CD4(+) T cells and has pleiotropic effects on immunity via the IL-21 receptor (IL-21R), a member of the common gamma chain (gamma(c)) cytokine receptor family. We show that IL-21 signaling plays a crucial role in T cell responses during Mycobacterium tuberculosis infection by augmenting CD8(+) T cell priming, promoting T cell accumulation in the lungs, and enhancing T cell cytokine production. In the absence of IL-21 signaling, more CD4(+) and CD8(+) T cells in chronically infected mice express the T cell inhibitory molecules PD-1 and TIM-3. We correlate these immune alterations with increased susceptibility of IL-21R(-/-) mice, which have increased lung bacterial burden and earlier mortality compared to WT mice. Finally, to causally link the immune defects with host susceptibility, we use an adoptive transfer model to show that IL-21R(-/-) T cells transfer less protection than WT T cells. These results prove that IL-21 signaling has an intrinsic role in promoting the protective capacity of T cells. Thus, the net effect of IL-21 signaling is to enhance host resistance to M. tuberculosis. These data position IL-21 as a candidate biomarker of resistance to tuberculosis., This work was supported by National Institutes of Health Grants R21 AI100766, R01 AI106725, and P01 AI073748.
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- 2016
19. TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection
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Chen Zhu, Ana C. Anderson, Katherine Steblenko, Samuel M. Behar, Pushpa Jayaraman, Britni L. Stowell, Vijay K. Kuchroo, Asaf Madi, and Miye K. Jacques
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0301 basic medicine ,Bacterial Diseases ,Physiology ,T-Lymphocytes ,Immune Receptors ,Biochemistry ,Cell-Mediated Immunity ,Mice ,White Blood Cells ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Cytotoxic T cell ,lcsh:QH301-705.5 ,Hepatitis A Virus Cellular Receptor 2 ,Innate Immune System ,Immune System Proteins ,biology ,T Cells ,Cell Differentiation ,3. Good health ,Interleukin-10 ,Actinobacteria ,medicine.anatomical_structure ,Infectious Diseases ,Receptors, Virus ,Cytokines ,Cellular Types ,Coreceptors ,medicine.drug ,Research Article ,Signal Transduction ,lcsh:Immunologic diseases. Allergy ,Interleukin 2 ,Tuberculosis ,T cell ,Immune Cells ,Immunology ,Cytotoxic T cells ,Microbiology ,Mycobacterium tuberculosis ,03 medical and health sciences ,Immune system ,Immunity ,Virology ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Blood Cells ,Bacteria ,Organisms ,Biology and Life Sciences ,Proteins ,CD coreceptors ,Cell Biology ,Molecular Development ,medicine.disease ,biology.organism_classification ,Tropical Diseases ,T Cell Receptors ,Chronic infection ,030104 developmental biology ,lcsh:Biology (General) ,Immune System ,Interleukin-2 ,Parasitology ,lcsh:RC581-607 ,Developmental Biology - Abstract
While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain–containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF but more IL-10, and are functionally exhausted. Finally, we show that TIM3 blockade restores T cell function and improves bacterial control, particularly in chronically infected susceptible mice. These data show that T cell immunity is suboptimal during chronic M. tuberculosis infection due to T cell exhaustion. Moreover, in chronically infected mice, treatment with anti-TIM3 mAb is an effective therapeutic strategy against tuberculosis., Author Summary Tuberculosis is a leading cause of morbidity and mortality across the globe. Fortunately, most people infected with M. tuberculosis mount a protective immune response and only a small fraction develops active disease. Impairment of immunity late during the course of disease can lead to bacterial recrudescence; however, why immunity fails is poorly understood. We investigated whether T cell exhaustion develops and contributes to immunological impairment during disease. Our studies provide definitive evidence that CD4+ T cells become functionally exhausted early after infection, and subsequently, CD8+ T cells also show signs of dysfunction. T cell exhaustion in both subsets was associated with the expression of multiple inhibitory receptors. Exhausted T cells expressed TIM3 plus other inhibitory receptors (e.g., PD1, TIM3, Lag-3, and 2B4), TIM3+PD1+ T cells were more likely to be poor producers of IL-2, IFNγ, and TNF and instead produce IL-10. Evaluation of gene expression by Nanostring confirmed that TIM3+PD1+ T cells in the lungs of infected mice had a transcriptional profile characteristic of exhausted T cells. Thus, this phenotype identified T cells that were truly exhausted and correlates well with previously established paradigm that co-expression of TIM3 with other inhibitory receptors such as PD1 contributes to impairment of T cell function during chronic inflammatory conditions. Most importantly, treatment of chronically infected mice with blocking antibodies specific for TIM3 led to a significant gain in bacterial control. Treatment was associated with an increase in IL-2, IFNγ, and TNF production by T cells. Based on this key result, we infer that TIM3-mediated T cell exhaustion impairs host resistance to M. tuberculosis. Thus, these data suggest that blockade of inhibitory T cell signals has the potential to be a therapeutic strategy against tuberculosis. The data in our report significantly advances our current knowledge of the biology of TIM3, the role of inhibitory T cell receptors during chronic infection, and the pathogenesis of tuberculosis.
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- 2015
20. Defining the contribution of T cell exhaustion to failed immunity during TB
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Miye K Jacques, Pushpa Jayaraman, Vijay K Kuchroo, and Samuel M Behar
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Immunology ,Immunology and Allergy - Abstract
Tuberculosis is a pulmonary disease, caused by Mycobacterium tuberculosis (Mtb) infection, which affects approximately one third of the global population and is a major public health concern. Although T cells are essential in mediating protection against Mtb infection, they are often unable to sterilize infected tissues. One possible reason for an ineffective immune response is the onset of T cell exhaustion or dysfunction. T cell exhaustion is characterized by the progressive loss of T cell effector function accompanied by an increase in expression of inhibitory receptors. Here we show that during Mtb infection, T cells express the inhibitory molecules Tim3 and PD1, and T cells that express both Tim3 and PD1 have decreased IFNγ and TNF production. In addition, antibody blockade of Tim3 improves T cell function and decreases bacterial burden. These results indicate that T cells are functionally exhausted during chronic Mtb infection and that blockade of inhibitory receptors can re-invigorate T cell function and improve the outcome of infection. Based on a possible role for CEACAM1 in the T cell inhibitory signal mediated by Tim3, we are currently performing experiments to determine how CEACAM1 affects host defense against Mtb. Understanding the roles of inhibitory receptors, such as Tim3 and PD1, during Mtb infection is providing insight into why T cell immunity is insufficient to eradicate Mtb infection.
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- 2016
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