IFNγR Pathway Mediates CAR T Cell Cytotoxicity Against Solid Tumors

The limited success of chimeric antigen receptor (CAR) T-cell therapy in solid tumors is, in part, due to external factors such as the immunosuppressive tumor microenvironment. However, the role that cell-intrinsic mechanisms may play in solid tumor resistant to CARs has yet to be fully elucidated. To identify genes that may contribute to CAR resistance, Larson and colleagues conducted a genome-wide CRISPR screen to induce insertion-deletion mutations in a human glioblastoma cell line and assessed resistance to CAR cytotoxicity using an EGFR-targeting CAR. As expected, genetic loss of EGFR as the CAR target contributed to the greatest survival advantage, but the other top five genes hit were related to the IFNγ pathway, including JAK2, IFNγR1, and IFNγR2. Single-gene knockouts of each gene were made, with each conferring resistance to CAR T-cell killing both in vitro and in vivo. Moreover, blockade of IFNγR1 also showed a reduction in the CAR T-cell killing of a patient-derived xenograft cell line, and CAR resistance was additionally observed upon treatment of tumor cells with the JAK1/2 inhibitor ruxolitinib. This resistance mechanism was found to extend beyond glioblastoma to other solid tumor types including pancreatic, ovarian, and lung cancers, but hematologic malignancies were not affected. IFNγR signaling in solid tumors was triggered by CAR T cell–produced IFNγ, and IFNγR-pathway knockouts demonstrated specific intrinsic resistance of the tumor cells to CAR-mediated cytotoxicity. Furthermore, differential expression in cell-adhesion pathway genes, specifically ICAM1, occurred in solid but not liquid tumors, with antibody-mediated ICAM1 blockade as well as genetic knockout of ICAM1 blocking the cytotoxicity of EGFR-targeting CARs. Conversely, reexpression of ICAM1 to similar levels as wild-type cells increased CAR binding cytotoxicity upon antigen exposure. Overall, this study reveals the critical role of IFNγR in mediating CAR T-cell efficacy in solid tumors and suggests optimization of T cell–tumor adhesion in future CAR T-cell designs.

Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM, Bouffard AA, et al. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours. Nature 2022;604:563–70.

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