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Mechanisms of TIGIT-driven immune suppression in cancer
  1. Sema Kurtulus1,
  2. Kaori Sakuishi2,
  3. Huiyuan Zhang1,
  4. Nicole Joller1,
  5. Dewar Tan1,
  6. Mark Smyth3,
  7. Vijay Kuchroo1 and
  8. Ana Anderson1
  1. Aff1 grid.62560.370000000403788294Center for Neurologic Diseases Brigham & Women's Hospital Boston MA USA
  2. Aff2 grid.26999.3d000000012151536XThe University of Tokyo Tokyo Japan
  3. Aff3 grid.1049.c0000000122941395Peter MacCallum Cancer CentreQueensland Institute of Medical Research Queensland Australia

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Meeting abstracts

TIGIT is a co-inhibitory molecule that limits T cell proliferation and activation. TIGIT expression has been recently shown to identify a subset of regulatory T cells (Treg) that specifically suppresses Th1 and Th17 responses; however its role in tumor immunity has not been examined. Here, we determined whether TIGIT has a role in the suppression of anti-tumor immune responses. We found that TIGIT is highly up-regulated on Treg and CD8+ tumor-infiltrating lymphocytes (TILs) in multiple pre-clinical cancer models. Importantly, TIGIT expression is strongly associated with expression of other co-inhibitory molecules; PD-1, Tim-3 and Lag-3 and with production of IL-10 in Treg and CD8+ TILs. Moreover, TIGIT+ CD8+ TILs display an exhausted phenotype determined by decreased production of IL-2 and TNF-α. To understand whether TIGIT acts as a checkpoint in anti-tumor response, we monitored growth of implanted B16 melanoma in TIGIT-/- mice and found that absence of TIGIT significantly delayed tumor growth. As TIGIT is expressed on both T cells (Treg and CD8+) and NK cells in cancer, we addressed the role of TIGIT in these subsets in driving immune suppression. Our data indicate that TIGIT may play a dominant role in Treg in that deficiency of TIGIT in Treg alone results in better control of tumor growth and a heightened proliferative response in the draining lymph nodes and spleens of tumor-bearing mice. Finally, we show that a TIGIT blocking antibody can be used therapeutically to decrease tumor growth and that blockade of TIGIT synergizes with Tim-3 blockade to maximally decrease tumor growth. Our study is the first report showing that TIGIT acts as an immune checkpoint in cancer. Importantly, our data indicate that TIGIT and Tim-3 synergize to suppress anti-tumor responses and targeting these two molecules could provide a therapeutic effect on tumor growth.