NK receptor signaling lowers the TCR activation threshold: role in selective recognition of cancer cells, but not healthy tissues, by TAA-specific CTLs 2687

Abstract Description CD28-driven costimulatory signal 2 allows naïve CD8+ T cells to selectively respond to tumor-associated antigens (TAA) presented by dendritic cells (DC), but not by non-professional antigen-presenting cells. In a sharp contrast, DC-primed cytotoxic T lymphocytes (CTL) bearing the same T cell receptor (TCR) as their naïve precursors target cancer cells in a CD28-independent fashion, due to the lack of CD28 ligands in non-hematological tumors. It remains elusive whether effector CTLs utilize alternative costimulatory pathways to enhance the antigen sensitivity and selectivity of their TCR. Here, we report that NK receptors (NKR) DNAM-1 and NKG2D replace CD28 in delivery of signal 2 to costimulate TCR-driven anti-cancer response of human effector CTLs. We found that DNAM-1, and to a lesser extend NKG2D, facilitated CTL activation by suboptimal TCR stimuli, resulting in enhanced CTL effector response and polyfunctionality. Using MART-1 and NY-ESO-1 as model TAAs, we showed that blockade of NKRs significantly impaired the CTL recognition and killing of antigen-low cancer cells. Analysis of melanoma samples further revealed that CTL-expression of NKRs was associated with effector status of CD8+ tumor-infiltrating lymphocytes and long-term survival. Enhancing NKR engagement by T cell genetic modifications strongly enhanced the killing of cancer cells, providing new means to develop more effective and selective adoptive T cell therapies. Funding Sources This work was supported by the NIH/NCI grants 1P01CA234212, 2P30A016056, 2P50CA159981, R50CA211108 and 1P50CA254865, DOD Grant BL4 W81XWH-19-1-0674, Rustum Family Foundation, Jacobs Family Foundation, Roswell Alliance Foundation and Roswell Park Institutional Funds. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)