Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074, Wuhan, China.
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China.
Nat Commun. 2022 Jan 11;13(1):231. doi: 10.1038/s41467-021-27936-8.
Therapeutic blockade of the immune checkpoint proteins programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has transformed cancer treatment. However, the overall response rate to these treatments is low, suggesting that immune checkpoint activation is not the only mechanism leading to dysfunctional anti-tumour immunity. Here we show that butyrophilin-like protein 2 (BTNL2) is a potent suppressor of the anti-tumour immune response. Antibody-mediated blockade of BTNL2 attenuates tumour progression in multiple in vivo murine tumour models, resulting in prolonged survival of tumour-bearing mice. Mechanistically, BTNL2 interacts with local γδ T cell populations to promote IL-17A production in the tumour microenvironment. Inhibition of BTNL2 reduces the number of tumour-infiltrating IL-17A-producing γδ T cells and myeloid-derived suppressor cells, while facilitating cytotoxic CD8 T cell accumulation. Furthermore, we find high BTNL2 expression in several human tumour samples from highly prevalent cancer types, which negatively correlates with overall patient survival. Thus, our results suggest that BTNL2 is a negative regulator of anti-tumour immunity and a potential target for cancer immunotherapy.
免疫检查点蛋白程序性细胞死亡蛋白 1（PD-1）和细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）的治疗性阻断已经改变了癌症治疗方法。然而，这些治疗的总体反应率较低，这表明免疫检查点的激活并不是导致肿瘤免疫功能障碍的唯一机制。在这里，我们表明 BTNL2（butyrophilin-like protein 2）是抗肿瘤免疫反应的有效抑制物。BTNL2 的抗体介导阻断可减弱多种体内小鼠肿瘤模型中的肿瘤进展，从而延长荷瘤小鼠的存活时间。从机制上讲，BTNL2 与局部 γδ T 细胞群相互作用，以促进肿瘤微环境中 IL-17A 的产生。BTNL2 的抑制减少了肿瘤浸润的产生 IL-17A 的 γδ T 细胞和髓源性抑制细胞的数量，同时促进了细胞毒性 CD8 T 细胞的积累。此外，我们在几种来自高流行癌症类型的人类肿瘤样本中发现了高表达的 BTNL2，其与总体患者生存率呈负相关。因此，我们的研究结果表明 BTNL2 是抗肿瘤免疫的负调节剂，也是癌症免疫治疗的潜在靶点。
