BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy

Author:

Pei Siyu1ORCID,Huang Mingzhu2ORCID,Huang Jia3ORCID,Zhu Xiaodong2ORCID,Wang Hui3ORCID,Romano Simona4ORCID,Deng Xiuyu1ORCID,Wang Yan1ORCID,Luo Yixiao2ORCID,Hao Shumeng1ORCID,Xu Jing1ORCID,Yu Tao1ORCID,Zhu Qingchen1ORCID,Yuan Jia1ORCID,Shen Kunwei5ORCID,Liu Zhiqiang6ORCID,Hu Guohong1ORCID,Peng Chao7ORCID,Luo Qingquan3ORCID,Wen Zhenzhen8ORCID,Dai Dongfang9ORCID,Xiao Yichuan1ORCID

Affiliation:

1. 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

2. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

3. Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

4. Department of Molecular Medicine and Medical Biotechnology, University of Naples, Federico II, Naples, Italy

5. Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

6. Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, School of Basic Medical Science, Tianjin Medical University, Tianjin, China.

7. National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai, China

8. Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

9. The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China

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.

Funder

National Key R&D Program of China

National Natural Science Foundation of China

Chinese Academy of Sciences

Shanghai Academic/Technology Research Leader

Zhejiang Provincial Medical and Health Science Foundation

Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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