Tumor cell-intrinsic stress states drive sensitivity to CAR T cell-therapy in pancreatic cancer [RNA-Seq]

The cellular and molecular factors that influence CAR T cell therapy response remain largely unknown. By integrating modular in vivo CRISPR screens with single cell genomics and immunocompetent orthotopic models of PDAC, we uncover oxidative and proteotoxic stress pathways as previously unknown tumor-intrinsic modulators of CAR T cell therapy response.

Disruption of stress-regulatory genes, particularly Keap1 and Slc33a1, sensitizes PDAC tumors to CAR T cell killing in vivo. Mechanistically, hyperactivation of the Nrf2 pathway by genetic ablation of the Keap1 tumor suppressor or endogenous engineering of a clinically observed Keap1 mutation enhances tumor susceptibility to CAR T cell therapy. Thus, tumor-intrinsic molecular stress phenotypes accompanying malignant tumor progression can induce unexpected cell state-specific vulnerabilities to cell-based immunotherapies.