- 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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Brigham and Women's Hospital
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