Location dependent phenotype and function of TIGIT expression on NK cells in mouse and human sarcoma models 4726

Abstract Description TIGIT has been identified as a key exhaustion marker on natural killer (NK) and T cells with implications for cancer immunotherapy. However, clinical results using TIGIT blockade have been disappointing. We sought to further characterize the differences in phenotype and function between TIGIT subsets for NK cells in cross-species sarcoma models. Human NK cells were flow sorted by TIGIT expression and co-cultured with IL-2 and feeder lines. Human and murine NK cells were analyzed from the blood/spleen and tumors of mice and sarcoma patients. Following sorting, human TIGIT+ NK cells expanded over 7 days at a significantly higher rate in culture and showed significantly less apoptosis. In PBMC-derived NK cells from sarcoma patients (N = 36), we observed statistically higher expression of CD69 and NKp46 in TIGIT+ compared to TIGIT- NK cells. whereas tumor-infiltrating NK cells showed greater dysfunction in TIGIT+ vs TIGIT- NK cells. Using BALB/c K7M2 osteosarcoma and C57BL/6 MCA-205 fibrosarcoma models, spleen derived TIGIT+ NK cells displayed a similar phenotype. When exposed to PMA, spleen derived TIGIT+ NK cells expressed significantly higher CD107a which was reversed in TIGIT+ tumor-infiltrating NK cells. Overall, our results suggest that TIGIT+ NK cells display increased activation, decreased apoptosis, and are more cytotoxic peripherally prior to becoming exhausted in the sarcoma tumor microenvironment with implications for how TIGIT block may be applied clinically. Funding Sources T2021-016 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)