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.

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。在这里，我们展示了 BTLA 对效应 T 细胞和 HVEM （TNFRSF14） 对免疫抑制肿瘤微环境细胞（即调节性 T 细胞）的相互作用的主要作用。嵌合抗原受体 （CAR） T 细胞中 BTLA 的高表达与对治疗的不良临床反应相关。因此，我们删除了 CAR T 细胞中的 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。从机制上讲，BTLA 在与 HVEM 反式结合时通过募集酪氨酸磷酸酶 SHP-1 和 SHP-2 来抑制 CAR T 细胞。因此，BTLA 敲除可促进 CAR 信号传导，从而增强效应器功能。总体而言，这些数据表明 BTLA-HVEM 轴是 CAR T 细胞免疫疗法中的关键免疫检查点，需要使用策略来克服这一障碍。