- PROJECT 1 Tim-3 was discovered in our laboratory as a molecule specifically expressed on terminally differentiated IFN-?- secreting CD4+ and CD8+ T cells. Our initial work showed that Tim-3 is required for the induction of antigen- specific tolerance and that blockade of Tim-3 exacerbates autoimmunity. Using a soluble Tim-3-Ig-fusion protein, we identified two molecular species that bind to Tim-3, one of which was resolved as Galectin-9 (Gal- 9). We then showed that Gal-9-triggering of Tim-3 induces cell death in IFN-?-secreting cells. These data led us to propose that Tim-3 is an inhibitory molecule that serves to contract inflammation driven by IFN-?- secreting T cells. Recent research from our group and others has extended the inhibitory role of Tim-3 to the dysfunctional/exhausted CD8+ T cells that arise in chronic viral infections and cancer. Importantly, blockade of Tim-3 signals restores function to exhausted T cells and improves clinical outcome. We have now identified that Tim-3 is also expressed on a highly suppressive population of FoxP3+ regulatory T cells (Treg) that are uniquely found in the tumor tissue of tumor-bearing hosts. Largely based on these data, therapies that target Tim-3 are currently being developed for cancer patients. Given these considerations, it is surprising how little is known regarding the signals that drive Tim-3 expression and how Tim-3 mediates its inhibitory function. Addressing these issues is critical to inform the clinical development of therapies that could successfully target Tim-3 for the treatment of human disease. We have now identified IL-27 as a key cytokine that drives Tim-3 expression and that lack of IL-27 signaling in vivo results in defective expression of Tim-3 on CD8+ tumor infiltrating lymphocytes (TILs), improved effector function in CD8+ T cells, and enhanced anti-tumor immunity. We have further made the novel discovery that carcinoembyronic antigen-related cell adhesion molecule-1 (CEACAM-1), is a novel Tim-3 ligand that binds to Tim-3 in cis to regulate TIM-3 expression and in trans to induce TIM-3 mediated inhibitory signals. Based on our preliminary data, we hypothesize that IL-27 dampens anti-tumor immunity by driving Tim-3 and CEACAM-1 expression to suppress CD8+ effector T cell responses and promote Treg-driven regulation of T cell responses in the tumor microenvironment. To address this hypothesis, we propose the following specific aims: 1) Determine the mechanism by which IL-27 drives T cell exhaustion and suppresses anti-tumor immunity. 2) Determine the regulation of the gene signature of Tim-3+ CD8+ T cells in cancer. 3) Determine the role of CEACAM-1 in regulating Tim-3 function in cancer.

Public Health Relevance

- PROJECT 1 Both cancer and chronic viral infection are chronic diseases that pose a significant health problem in the United States. Dysfunctional or exhausted T cells arise in both of these chronic diseases and present a barrier to successful viral and tumor clearance. In the proposed studies, we will determine how the inhibitory molecule Tim-3 promotes T cell dysfunction/exhaustion in cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI073748-08
Application #
9278088
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
8
Fiscal Year
2017
Total Cost
$396,839
Indirect Cost
$155,105
Name
Brigham and Women's Hospital
Department
Type
Independent Hospitals
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Meyer Zu Horste, Gerd; Przybylski, Dariusz; Schramm, Markus A et al. (2018) Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1. Immunity 48:556-569.e7
Iyer, Shankar S; Gensollen, Thomas; Gandhi, Amit et al. (2018) Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses. Cell 173:1123-1134.e11
Chihara, Norio; Madi, Asaf; Kondo, Takaaki et al. (2018) Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558:454-459
Dixon, Karen O; Schorer, Michelle; Nevin, James et al. (2018) Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity. J Immunol 200:3000-3007
Wu, Chuan; Chen, Zuojia; Xiao, Sheng et al. (2018) SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells. Cell Rep 22:653-665
Sabatos-Peyton, Catherine A; Nevin, James; Brock, Ansgar et al. (2018) Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy. Oncoimmunology 7:e1385690
Dougall, William C; Kurtulus, Sema; Smyth, Mark J et al. (2017) TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol Rev 276:112-120
Boggiano, Cesar; Eichelberg, Katrin; Ramachandra, Lakshmi et al. (2017) ""The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design"" - Meeting report. Vaccine 35:3433-3440
Carpenter, Stephen M; Yang, Jason D; Lee, Jinhee et al. (2017) Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis. PLoS Pathog 13:e1006704
Wang, Chao; Singer, Meromit; Anderson, Ana C (2017) Molecular Dissection of CD8+ T-Cell Dysfunction. Trends Immunol 38:567-576

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