RNF19B confers tumor resistance to CAR T cells
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Chimeric antigen receptor (CAR) T cells have transformed cancer therapy, yet many tumors remain refractory. To uncover broadly acting mechanisms of resistance, we performed genome-wide CRISPR activation screens across diverse cancer cell types. These screens converged on RNF19B, an E3 ubiquitin ligase whose high expression correlates with poor patient survival and confers robust CAR-T resistance in mouse xenograft models. Mechanistically, RNF19B destabilizes the interferon-γ receptor subunit IFNGR1, blunting interferon-γ signaling, and simultaneously induces CAMKK2, which mediates resistance through an independent pathway. Pharmacologic inhibition of CAMKK2 synergized with CAR-T therapy in different xenograft mouse models. Our findings identify RNF19B as a previously unrecognized, dual-pathway mediator of CAR-T resistance and reveal CAMKK2 inhibition as a potential strategy to enhance CAR-T efficacy.
