The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer

• 成果类型: Article
• 署名作者: Feng, Bing; Bai, Zhiliang; Zhou, Xiaolei; Zhao, Yang; Xie, Yu-Qing; Huang, Xinyi; Liu, Yang; Enbar, Tom; Li, Rongrong; Wang, Yi; Gao, Min; Bonati, Lucia; Peng, Mei-Wen; Li, Weilin; Tao, Bo; Charmoy, Melanie; Held, Werner; Melenhorst, J. Joseph; Fan, Rong; Guo, Yugang; Tang, Li
• 署名单位: Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Yale University; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Yale University; University of Lausanne; Cleveland Clinic Foundation; Zhejiang University; Zhejiang University; Zhejiang University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6437
• DOI: 10.1038/s41586-024-07962-4
• 发表日期: 2024-10-17
• 页码: 712-+
• 关键词: apoptosis; efficacy; immunity

摘要

Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon(1,2). A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer(3,4). Here we show that an interleukin-4 fusion protein (Fc-IL-4), a typical type 2 cytokine, directly acts on CD8(+) T cells and enriches functional terminally exhausted CD8(+) T (CD8(+) T-TE) cells in the tumour. Consequently, Fc-IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc-IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8(+) TTE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc-IL-4 is indispensable for reinvigorating intratumoural CD8(+) T-TE cells. These findings underscore Fc-IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.