Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
J Exp Med. 2021 Jul 5;218(7). doi: 10.1084/jem.20202144.
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.
TGFβ 对于抗肿瘤 Th9 细胞的产生至关重要；另一方面，它会导致抗肿瘤免疫的抵抗。尽管最近取得了进展，但在 Th9 介导的癌症免疫治疗中协调 TGFβ 信号的双刃剑效应的潜在机制仍难以捉摸。在这里，我们发现 TGFβ 诱导的双功能凋亡调节剂（BFAR）下调代表了防止 TGFβ 信号持续激活并因此损害 Th9 诱导能力的关键机制。从机制上讲，BFAR 介导 TGFβR1 在 K268 处的 K63 连接泛素化，这对于激活 TGFβ 信号至关重要。因此，BFAR 缺失或 K268R 敲入突变会抑制 TGFβR1 泛素化和 Th9 分化，从而抑制 Th9 介导的癌症免疫治疗。更有趣的是，BFAR 过表达的 Th9 细胞表现出有希望的治疗效果，可以遏制肿瘤生长和转移，并促进抗 PD-1 介导的检查点免疫治疗的敏感性。因此，我们的发现确立了 BFAR 作为一个关键的 TGFβ 调节基因，可微调 TGFβ 信号，导致 Th9 诱导不敏感，并强调了 BFAR 在促进 Th9 介导的癌症免疫治疗中的转化潜力。
