C-Jun overexpression overcomes CAR-T cell resistance to checkpoint blockade and improves efficacy in lung adenocarcinoma

ABSTRACT: CAR-T cell therapy has induced dramatic responses in hematological malignancies, but extending this success to more common epithelial cancers has proved more challenging. We previously showed that CAR-T cells targeting the tumor-associated antigen ROR1 became terminally exhausted in breast and lung cancer patients, indicating strategies to preserve CAR-T function are needed. We developed an autochthonous model of ROR1+ lung cancer that recapitulates the suppressive microenvironment of human cancer and dysfunction of ROR1 CAR-T cells observed in patients. Surprisingly, despite high accumulation of PD-1+ CAR-T cells and PD-L1+ cells within murine tumors, PD-L1 blockade did not enhance ROR1 CAR-T activity and instead drove their terminal differentiation and more rapid attrition within tumors. Overexpression of the AP-1 subunit c-Jun, which has been shown to prevent CAR-T cell exhaustion in xenograft models, significantly improved ROR1 CAR-T accumulation, function, and differentiation into PD-1+Tcf1+ stem-like exhausted cells, which have been shown to mediate responses to PD-1/PD-L1 axis blockade. Though c-Jun overexpression alone was unable to prevent ROR1 CAR-T exhaustion in this highly aggressive model, it dramatically sensitized CAR-T cells to enhancement with PD-L1 blockade. In contrast to its effects on ROR1 CAR-T cells, PD-L1 blockade drove a log-fold increase in tumor-infiltrating CAR-T cells overexpressing c-Jun without inducing their terminal differentiation, resulting in nearly complete eradication of ROR1+ tumor. Mechanistically, loss of c-Jun CAR-T cell function correlated with post-transcriptional downregulation of c-Jun that could be restored through PD-L1 blockade. Altogether, our data indicate that c-Jun overexpression may serve as a readily translatable strategy to sensitize CAR-T cells to enhancement with checkpoint blockade.

ORGANISM(S): Mus musculus

PROVIDER: GSE288687 | GEO | 2025/02/04

REPOSITORIES: GEO