Grant: Project Grant

Cancer cells can acquire features that allow them to evade recognition and destruction by effector cells of the immune system known as cytotoxic T lymphocytes (CTLs). These features or phenotypic changes not only facilitate progressive expansion and dissemination of cancer cells from within the tumor, but also promote resistance to currently employed immunotherapies that harness the potent cytotoxic properties of CTLs, including checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. The use of traditional genomic approaches (especially genome sequencing) to characterize patient cohorts treated with immunotherapy has provided fundamental insight into several mechanisms that promote immune evasion. Central to these genetic alterations that allow cancer cells to directly escape CTL killing, a form of immune evasion, includes loss of antigen presentation machinery and defects in cytokine signaling (e.g. interferon, TNF). While these landmark studies underscore the need to understand cancer intrinsic CTL evasion, they are limited to detecting only frequently occurring genetic alterations that contribute to this hallmark of cancer. As such, there remains a paucity of data systematically cataloging how individual cancer cell genetic elements act in a coordinated fashion to facilitate cancer intrinsic CTL evasion. Our research proposal aims to chart genetic dependencies that contribute to cancer intrinsic CTL evasion; to understand how core genetic dependencies that contribute to tumor heterogeneity in vivo and the tumor immune microenvironment, including in the presence of immune checkpoint blockade; to determine how our murine results translate to human cancer models; and to map genes that can overcome mutations that promote resistance to CTL toxicity using a combinatorial CRISPR targeting system recently developed in the lab.