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

Bing Feng, Zhiliang Bai, Xiaolei Zhou, Yang Zhao, Yu-Qing 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 () and Li Tang ()
Additional contact information
Bing Feng: École Polytechnique Fédérale de Lausanne (EPFL)
Zhiliang Bai: Yale University
Xiaolei Zhou: École Polytechnique Fédérale de Lausanne (EPFL)
Yang Zhao: École Polytechnique Fédérale de Lausanne (EPFL)
Yu-Qing Xie: École Polytechnique Fédérale de Lausanne (EPFL)
Xinyi Huang: EPFL
Yang Liu: École Polytechnique Fédérale de Lausanne (EPFL)
Tom Enbar: École Polytechnique Fédérale de Lausanne (EPFL)
Rongrong Li: École Polytechnique Fédérale de Lausanne (EPFL)
Yi Wang: École Polytechnique Fédérale de Lausanne (EPFL)
Min Gao: École Polytechnique Fédérale de Lausanne (EPFL)
Lucia Bonati: École Polytechnique Fédérale de Lausanne (EPFL)
Mei-Wen Peng: École Polytechnique Fédérale de Lausanne (EPFL)
Weilin Li: École Polytechnique Fédérale de Lausanne (EPFL)
Bo Tao: Yale University School of Medicine
Mélanie Charmoy: University of Lausanne
Werner Held: University of Lausanne
J. Joseph Melenhorst: Cleveland Clinic
Rong Fan: Yale University
Yugang Guo: École Polytechnique Fédérale de Lausanne (EPFL)
Li Tang: École Polytechnique Fédérale de Lausanne (EPFL)

Nature, 2024, vol. 634, issue 8034, 712-720

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07962-4

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