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. 2024 Jun;25(6):1020-1032.
doi: 10.1038/s41590-024-01847-4. Epub 2024 Jun 3.

The BTLA-HVEM axis restricts CAR T cell efficacy in cancer

Puneeth Guruprasad  1   2   3   4 , Alberto Carturan  2   3   4 , Yunlin Zhang  2   3   4 , Jong Hyun Cho  5 , Kingsley Gideon Kumashie  6 , Ruchi P Patel  2   3   4 , Ki-Hyun Kim  7 , Jong-Seo Lee  7 , Yoon Lee  7 , Jong Hoon Kim  7 , Junho Chung  8 , Akshita Joshi  2   4 , Ivan Cohen  2   3   4 , Maksim Shestov  2   3   4 , Guido Ghilardi  2   3   4 , Jaryse Harris  2   3   4   9 , Raymone Pajarillo  2   3   4 , Mathew Angelos  2   3   4 , Yong Gu Lee  2   3   4   10 , Shan Liu  11 , Jesse Rodriguez  2   4 , Michael Wang  2   3   4 , Hatcher J Ballard  3   4 , Aasha Gupta  2   4 , Ositadimma H Ugwuanyi  2   3   4 , Seok Jae Albert Hong  2   3   4 , Audrey C Bochi-Layec  2   3   4 , Christopher T Sauter  2   3   4 , Linhui Chen  2   3   4 , Luca Paruzzo  2   3   4 , Shane Kammerman  6 , Olga Shestova  2   3   4 , Dongfang Liu  5 , Laura A Vella  6 , Stephen J Schuster  3   4 , Jakub Svoboda  3   4 , Patrizia Porazzi  2   3   4 , Marco Ruella  12   13   14   15
Affiliations

The BTLA-HVEM axis restricts CAR T cell efficacy in cancer

Puneeth Guruprasad et al. Nat Immunol. 2024 Jun.

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.

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