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

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

doi:10.1038/s41590-024-01847-4

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

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Pages (from-to)	1020-1032
Number of pages	13
Journal	Nature Immunology
Volume	25
Issue number	6
DOIs	https://doi.org/10.1038/s41590-024-01847-4
State	Published - Jun 2024

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Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

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Guruprasad, P., Carturan, A., Zhang, Y., Cho, J. H., Kumashie, K. G., Patel, R. P., Kim, K. H., Lee, J. S., Lee, Y., Kim, J. H., Chung, J., Joshi, A., Cohen, I., Shestov, M., Ghilardi, G., Harris, J., Pajarillo, R., Angelos, M., Lee, Y. G., ... Ruella, M. (2024). The BTLA–HVEM axis restricts CAR T cell efficacy in cancer. Nature Immunology, 25(6), 1020-1032. https://doi.org/10.1038/s41590-024-01847-4

@article{8ed063ff89ec4607b0b63610029ada39,

title = "The BTLA–HVEM axis restricts CAR T cell efficacy in cancer",

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.",

author = "Puneeth Guruprasad and Alberto Carturan and Yunlin Zhang and Cho, {Jong Hyun} and Kumashie, {Kingsley Gideon} and Patel, {Ruchi P.} and Kim, {Ki Hyun} and Lee, {Jong Seo} and Yoon Lee and Kim, {Jong Hoon} and Junho Chung and Akshita Joshi and Ivan Cohen and Maksim Shestov and Guido Ghilardi and Jaryse Harris and Raymone Pajarillo and Mathew Angelos and Lee, {Yong Gu} and Shan Liu and Jesse Rodriguez and Michael Wang and Ballard, {Hatcher J.} and Aasha Gupta and Ugwuanyi, {Ositadimma H.} and Hong, {Seok Jae Albert} and Bochi-Layec, {Audrey C.} and Sauter, {Christopher T.} and Linhui Chen and Luca Paruzzo and Shane Kammerman and Olga Shestova and Dongfang Liu and Vella, {Laura A.} and Schuster, {Stephen J.} and Jakub Svoboda and Patrizia Porazzi and Marco Ruella",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = jun,

doi = "10.1038/s41590-024-01847-4",

language = "English",

volume = "25",

pages = "1020--1032",

journal = "Nature Immunology",

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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 & Ruella, M 2024, 'The BTLA–HVEM axis restricts CAR T cell efficacy in cancer', Nature Immunology, vol. 25, no. 6, pp. 1020-1032. https://doi.org/10.1038/s41590-024-01847-4

TY - JOUR

T1 - The BTLA–HVEM axis restricts CAR T cell efficacy in cancer

AU - Guruprasad, Puneeth

AU - Carturan, Alberto

AU - Zhang, Yunlin

AU - Cho, Jong Hyun

AU - Kumashie, Kingsley Gideon

AU - Patel, Ruchi P.

AU - Kim, Ki Hyun

AU - Lee, Jong Seo

AU - Lee, Yoon

AU - Kim, Jong Hoon

AU - Chung, Junho

AU - Joshi, Akshita

AU - Cohen, Ivan

AU - Shestov, Maksim

AU - Ghilardi, Guido

AU - Harris, Jaryse

AU - Pajarillo, Raymone

AU - Angelos, Mathew

AU - Lee, Yong Gu

AU - Liu, Shan

AU - Rodriguez, Jesse

AU - Wang, Michael

AU - Ballard, Hatcher J.

AU - Gupta, Aasha

AU - Ugwuanyi, Ositadimma H.

AU - Hong, Seok Jae Albert

AU - Bochi-Layec, Audrey C.

AU - Sauter, Christopher T.

AU - Chen, Linhui

AU - Paruzzo, Luca

AU - Kammerman, Shane

AU - Shestova, Olga

AU - Liu, Dongfang

AU - Vella, Laura A.

AU - Schuster, Stephen J.

AU - Svoboda, Jakub

AU - Porazzi, Patrizia

AU - Ruella, Marco

PY - 2024/6

Y1 - 2024/6

N2 - 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.

AB - 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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U2 - 10.1038/s41590-024-01847-4

DO - 10.1038/s41590-024-01847-4

M3 - Article

C2 - 38831106

AN - SCOPUS:85194997299

SN - 1529-2908

VL - 25

SP - 1020

EP - 1032

JO - Nature Immunology

JF - Nature Immunology

IS - 6

ER -

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

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