1. The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.
- Author
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Guruprasad P, Carturan A, Zhang Y, Cho JH, Kumashie KG, Patel RP, Kim KH, Lee JS, Lee Y, Kim JH, Chung J, Joshi A, Cohen I, Shestov M, Ghilardi G, Harris J, Pajarillo R, Angelos M, Lee YG, Liu S, Rodriguez J, Wang M, Ballard HJ, Gupta A, Ugwuanyi OH, Hong SJA, Bochi-Layec AC, Sauter CT, Chen L, Paruzzo L, Kammerman S, Shestova O, Liu D, Vella LA, Schuster SJ, Svoboda J, Porazzi P, and Ruella M
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Mice, Knockout, Neoplasms immunology, Neoplasms therapy, Signal Transduction, T-Lymphocytes, Regulatory immunology, Immunotherapy, Adoptive methods, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen metabolism, Receptors, Chimeric Antigen genetics, Receptors, Immunologic metabolism, Receptors, Immunologic genetics, Receptors, Tumor Necrosis Factor, Member 14 metabolism, Receptors, Tumor Necrosis Factor, Member 14 immunology, Receptors, Tumor Necrosis Factor, Member 14 genetics, Tumor Microenvironment immunology
- Abstract
The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2024
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