Unveiling Human Cancer Cell Intrinsic Pathways Impacting T Cell Recognition and Killing via Genome-Wide CRISPR Screening

Genetic screening is a powerful tool for uncovering therapeutic targets in cancer, including those that leverage anti-tumor immune responses. However, existing immune-modulating screens are largely restricted to a small set of human or murine cancer models. In this study, we conducted genome-wide CRISPR screening across 47 diverse human cancer cell lines using an antigen-dependent human cancer/T cell co-culture assay. This unbiased approach uncovered numerous known and novel pathways in cancer cells that influence T cell recognition and killing. Notably, we identified a gene pair, PAXIP1 and PAGR1, whose disruption sensitized multiple cancer cell lines to T cell-mediated killing. Mechanistical studies revealed that loss of PAXIP1 and PAGR1 enhances cancer cell susceptibility to death ligand-induced extrinsic apoptosis, primarily by modulating the DNA damage response. Importantly, the interaction between PAXIP1 and PAGR1 was found to be critical, underscoring the potential for enhancing anti-tumor immune responses through targeting this interaction.