美国宾夕法尼亚大学Marco Ruella团队近日取得一项新成果。他们发现BTLA-HVEM轴限制了CAR-T细胞在癌症中的疗效。该研究于2024年6月3日发表于国际一流学术期刊《自然—免疫学》杂志上。

据了解，基于T细胞的免疫疗法的疗效，受到肿瘤微环境中免疫抑制压力的限制。

本研究表明，BTLA作用于效应T细胞，而HVEM (TNFRSF14)作用于免疫抑制性肿瘤微环境细胞(即调节性T细胞)，二者之间的相互作用发挥了主导作用。嵌合抗原受体(CAR) T细胞中高BTLA表达与临床治疗反应差相关。因此，该研究团队在CAR-T细胞中删除了BTLA，并在淋巴瘤和实体恶性肿瘤模型中显示出更好的肿瘤控制和持久性。

在机制上，BTLA通过与HVEM反式结合，通过募集酪氨酸磷酸酶SHP-1和SHP-2来抑制CAR-T细胞。敲除BTLA可促进CAR信号传导，进而增强效应功能。总的来说，这些数据表明BTLA-HVEM轴是CAR-T细胞免疫治疗中一个至关重要的免疫检查点，因此需要采用相应的策略来克服这一障碍。

附：英文原文

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

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

Issue&Volume: 2024-06-03

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.

DOI: 10.1038/s41590-024-01847-4

Source: https://www.nature.com/articles/s41590-024-01847-4