Andrew Snyder, Sarah M. Garrison, Mitchell G. Kluesner, W. Sam Nutt, Carolyn Shasha, T. T. Giang Ho, Sydney A. Marsh, Miles H. Linde, Feinan Wu, Lauren K. Meyer, Amelia R. Wilhelm, Sergio Ortiz-Espinosa, Victor Zepeda, Emma Bingham, Haleema S. Malik, Sam R. Mak, Ekram Gad, Shruti S. Bhise, Everett T Fan, Megha Sarvothama, Xiao Wang, Shobha Potluri, Annalyssa Long, Anna Elz, Cyrus M. Ghajar, Scott N. Furlan, Evan W. Newell, Shivani Srivastava
Chimeric antigen receptor T (CAR T) cell therapy has shown limited synergy with immune checkpoint inhibitors, but the mechanisms underlying resistance remain unclear. Stemlike T cells coexpressing programmed cell death protein 1 (PD-1) and T cell factor 1 (TCF1) mediate responses to PD-1–PD-L1 (programmed death ligand 1) blockade and are maintained by major histocompatibility complex (MHC)–dependent interactions with dendritic cells in lymphoid tissues. Because CAR T cells recognize intact antigen rather than peptide-MHC, their activation is restricted to tumors, potentially limiting maintenance of this critical subset. In murine models of lung cancer, CAR T cells down-regulated TCF1, became exhausted, and were not enhanced by PD-L1 blockade. Overexpression of the transcription factor c-Jun increased intratumoral PD-1 + TCF1 + CAR T cells but did not prevent exhaustion, given that PD-1 induced posttranscriptional c-Jun down-regulation. PD-L1 blockade restored c-Jun levels, markedly increased CAR T cells, and enabled near-complete tumor clearance, revealing a mechanism by which MHC-independent CAR T cells can be engineered to overcome resistance to PD-1–PD-L1 blockade.