Pei Siyu, Deng Xiuyu, Yang Ruirui, Wang Hui, Shi Jian-Hong, Wang Xueqing, Huang Jia, Tian Yu, Wang Rongjing, Zhang Sulin, Hou Hui, Xu Jing, Zhu Qingcheng, Huang Huan, Ye Jialing, Wang Cong-Yi, Lu Wei, Luo Qingquan, Ni Zhi-Yu, Zheng Mingyue, Xiao Yichuan
Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Nat Aging. 2024 Dec;4(12):1828-1844. doi: 10.1038/s43587-024-00746-5. Epub 2024 Nov 26.
Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8 tissue resident memory T (T) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8 T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8 T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated T reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8 T cells by restoring T generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8 T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced T restriction as a key mechanism causing aged CD8 T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy.
衰老会损害抗肿瘤免疫力，但其潜在机制仍不清楚。在此，我们报告衰老会损害小鼠非淋巴组织中CD8组织驻留记忆T（TRM）细胞的生成，从而损害衰老CD8 T细胞的抗肿瘤活性，这一现象在人类肺腺癌中也有观察到。我们进一步确定，凋亡调节因子BFAR在衰老的CD8 T细胞中高度富集，其中BFAR通过激活JAK2去泛素化抑制细胞因子诱导的JAK2信号传导，从而限制下游STAT1介导的T细胞重编程。通过敲除Bfar或用我们开发的BFAR抑制剂iBFAR2处理来靶向BFAR，可通过恢复肿瘤微环境中的TRM生成来挽救衰老CD8 T细胞的抗肿瘤活性，从而在衰老CD8 T细胞转移和抗程序性细胞死亡蛋白1（PD-1）耐药小鼠肿瘤模型中有效抑制肿瘤生长。总之，我们的研究结果确定BFAR诱导的TRM限制是导致衰老CD8 T细胞功能障碍的关键机制，并突出了iBFAR2在恢复老年个体或抗PD-1治疗耐药患者抗肿瘤活性方面的转化潜力。
