CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
BTLA-HVEM 轴限制 CAR-T 细胞在肿瘤中的疗效
英文原题：The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.
查看英文原题
The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.
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中文摘要
T 细胞免疫疗法的疗效受到肿瘤微环境免疫抑制压力的限制。本研究显示，效应 T 细胞上的 BTLA 与免疫抑制性肿瘤微环境细胞（即调节性 T 细胞）上的 HVEM（TNFRSF14）之间的相互作用发挥主导作用。嵌合抗原受体（CAR）T 细胞中 BTLA 高表达与较差临床治疗反应相关。因此，我们在 CAR-T 细胞中敲除 BTLA，并发现其在淋巴瘤和实体恶性肿瘤模型中的肿瘤控制能力和持续存留能力均有所改善。在机制上，BTLA 与 HVEM 发生反式结合后募集酪氨酸磷酸酶 SHP-1 和 SHP-2，从而抑制 CAR-T 细胞。敲除 BTLA 因此可增强 CAR 信号传导，进而改善效应功能。总体而言，这些数据表明 BTLA-HVEM 轴是 CAR-T 细胞免疫治疗中的关键免疫检查点，应考虑采用策略克服这一屏障。
展开英文摘要原文
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.
论文信息
- 作者
- Guruprasad P、Carturan A、Zhang Y、Cho JH、Kumashie KG、Patel RP、Kim KH、Lee JS
- 第一作者单位
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.United States
- 通讯作者单位
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. mruella@upenn.edu.United States
- 期刊
- Nature immunology2024 Jun
- 原文标识
- PubMed 38831106 · DOI 10.1038/s41590-024-01847-4