BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy
Siyu Pei, Mingzhu Huang, Jia Huang, Xiaodong Zhu, Hui Wang, Simona Romano, Xiuyu Deng, Yan Wang, Yixiao Luo, Shumeng Hao, Jing Xu, Tao Yu, Qingchen Zhu, Jia Yuan, Kunwei Shen, Zhiqiang Liu, Guohong Hu, Chao Peng, Qingquan Luo, Zhenzhen Wen, Dongfang Dai, Yichuan Xiao
Abstract
TGFβ is essential for the generation of anti-tumor Th9 cells; on the other hand, it causes resistance against anti-tumor immunity. Despite recent progress, the underlying mechanism reconciling the double-edged effect of TGFβ signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFβ-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFβ signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFβR1 at K268, which is critical to activate TGFβ signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFβR1 ubiquitination and Th9 differentiation, thereby inhibiting Th9-mediated cancer immunotherapy. More interestingly, BFAR-overexpressed Th9 cells exhibit promising therapeutic efficacy to curtail tumor growth and metastasis and promote the sensitivity of anti-PD-1-mediated checkpoint immunotherapy. Thus, our findings establish BFAR as a key TGFβ-regulated gene to fine-tune TGFβ signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy.