A GENOME-SCALE CRISPR SCREEN TO IDENTIFY ESSENTIAL GENES FOR THE EFFECTOR FUNCTION OF CYTOTOXIC T LYMPHOCYTES

Abstract

Somatic gene mutations and dysregulations can alter the vulnerability of a cancer cell to T cell based immune selection. To systematically identify genes that positively regulate the sensitivity of cancer cells to T cell-mediated cytolysis, we developed a two cell-type (2CT) functional screening platform by combining human T cell engineering and CRISPR (Clustered regularly interspaced short palindromic repeats) genome editing. Using the 2CT genome-scale perturbation screen in melanoma cells, we identified and validated multiple genes whose loss impaired the effector function of T cells. Moreover, we uncover a group of genes from these screens that correlates with cytolytic activity across the majority of the cancer types, reflecting context independence of these genes in the modulation of inherent T cell responses in multiple cancers. This study demonstrates the broad applicability of 2CT CRISPR screens to study the interaction of cancer cells with immune cells and identify novel therapeutic targets for cellular therapies.