ROR1 CAR T cells infiltrated ROR1+ NSCLC mouse tumors, but lost TCF1 expression and failed to maintain a progenitor exhausted (Tpex) population. The addition of anti-PD-L1 did not improve CAR T cell counts or efficacy, and further drove exhaustion. Snyder et al. found that co-delivery of c-Jun by the ROR1 CAR transiently increased CAR-T tumor accumulation and Tpex phenotype, and combining with anti-PD-L1 further improved tumor T cell counts, c-Jun expression, phenotype, and efficacy. Spatial transcriptomics found that c-Jun CAR-T were distributed throughout lung tumors, proximal to PD-L1+ myeloid cells, and Tpex-enriched relative to standard CAR-T.
Contributed by Alex Najibi
ABSTRACT: 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.
Author Info: (1) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. Medical Sc
Author Info: (1) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. Medical Scientist Training Program, University of Washington, Seattle, WA, USA. (2) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (3) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. Medical Scientist Training Program, University of Washington, Seattle, WA, USA. (4) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. (5) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (6) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (7) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Department of Immunology, University of Washington, Seattle, WA, USA. (8) Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA,USA. (9) Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Center, Seattle, WA, USA. (10) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (11) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. Medical Scientist Training Program, University of Washington, Seattle, WA, USA. (12) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (13) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (14) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (15) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Invent Program, Seattle Children's Research Institute, Seattle, WA, USA. (16) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (17) Comparative Medicine, Translational Research Model Services, Fred Hutchinson Cancer Center, Seattle, WA, USA. (18) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (19) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (20) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (21) Lyell Immunopharma, South San Francisco, CA, USA. (22) Lyell Immunopharma, South San Francisco, CA, USA. (23) Fred Hutch Innovation Lab, Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, USA. (24) Fred Hutch Innovation Lab, Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, USA. (25) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA,USA. Center for Metastasis Research eXcellence (MET-X), Fred Hutchinson Cancer Center, Seattle, WA, USA. (26) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (27) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (28) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Department of Immunology, University of Washington, Seattle, WA, USA.
