387 Adaptive Priming Meets Innate Killing: TCR-Activated CD8+ T Cells Can Kill Tumor Cells in an MHC-Independent Manner via NKG2D

INTRODUCTION: The accepted paradigm for antitumor immunity relies upon tumor cell kill by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex class I (MHC-I) molecules. METHODS: We sought to better evaluate the role of MHC-I expression within the tumor microenvironment. RESULTS: T cell-activating immunotherapies, surprisingly, remained effective against glioma and melanoma lines engineered to lack MHC-I expression. Such efficacy proved independent of NK cells and, instead, relies consistently upon CD8+ T cell-mediated cytotoxicity, despite the absence of MHC-I on tumor targets. This cytotoxicity is both antigen- and MHC-agnostic and, instead, is mediated by T cell NKG2D engagement of NKG2D ligands on tumor cells, which are upregulated on MHC-loss variants. Necessarily, tumor cell kill in these instances is antigen-independent, although prior T cell receptor activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumors cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice, as well as in vitro in human tumor systems, and are obviated by NKG2D knockout or blockade. Tumor cell killing following T cell NKG2D engagement is Fas-independent and appears to involve granzyme. CONCLUSIONS: Such findings challenge the traditional model of T cell-mediated tumor immunity and likewise identify the NKG2D/NKG2DL axis as a novel therapeutic target for enhancing T cell killing of MHC loss variants.