细胞毒性T细胞
细胞因子
免疫学
CD8型
生物
免疫系统
体外
遗传学
作者
Bing Feng,Zhiliang Bai,Xiaolei Zhou,Yang Zhao,Yuqing Xie,Xinyi Huang,Yang Liu,Tom Enbar,Rongrong Li,Yi Wang,Min Gao,Lucia Bonati,Mei-Wen Peng,Weilin Li,Bo Tao,Mélanie Charmoy,Werner Held,J. Joseph Melenhorst,Rong Fan,Yugang Guo
出处
期刊:Nature
[Nature Portfolio]
日期:2024-09-25
卷期号:634 (8034): 712-720
被引量:110
标识
DOI:10.1038/s41586-024-07962-4
摘要
Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer3,4. 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+ TTE) 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+ TTE 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.
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