The ability of cells of the immune system, in particular CD8+ cytotoxic T-cells and natural killer (NK) cells, to kill tumor cells in vivo is now being exploited in the clinic with the advent of immunotherapy. While these therapies are effective in a subset of patients the emergence of tumor resistance is now being observed in the clinic. Several studies have investigated tumour evasion from CD8+ cytotoxic T-cell directed killing; however, it is not known if the same mechanisms apply for the tumor cells to evade NK cells. For instance, one major pathway of CD8+ cytotoxic T-cell resistance is via alteration of the MHC class I antigen presentation pathway which could in theory allow the tumor cells to become more sensitive to NK cell mediated killing due to “loss of self.” We have investigated tumor cell intrinsic NK cell resistance and sensitivity pathways using genome-wide CRISPR-Cas9 loss of function in vitro screens. These screens have confirmed the essential role of cell adhesion via ICAM1 in enabling tumor cell killing by NK cells. We have also identified other novel pathways that could be manipulated to enhance tumor cell cytotoxicity and the development of alternative and/or additive therapeutic strategies in the clinic.

Citation Format: Carmen Ballesteros Reviriego, Anneliese O. Speak, Gemma Turner, Vivek Iyer, Leopold Parts, David J. Adams. Identification of tumor cell intrinsic immune evasion mechanisms [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B145.