The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8<sup>+</sup> T cells against cancer.

Details

Serval ID
serval:BIB_8B9B2D07B620
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8<sup>+</sup> T cells against cancer.
Journal
Nature
Author(s)
Feng B., Bai Z., Zhou X., Zhao Y., Xie Y.Q., Huang X., Liu Y., Enbar T., Li R., Wang Y., Gao M., Bonati L., Peng M.W., Li W., Tao B., Charmoy M., Held W., Melenhorst J.J., Fan R., Guo Y., Tang L.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
10/2024
Peer-reviewed
Oui
Volume
634
Number
8034
Pages
712-720
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon <sup>1,2</sup> . A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer <sup>3,4</sup> . Here we show that an interleukin-4 fusion protein (Fc-IL-4), a typical type 2 cytokine, directly acts on CD8 <sup>+</sup> T cells and enriches functional terminally exhausted CD8 <sup>+</sup> T (CD8 <sup>+</sup> T <sub>TE</sub> ) 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 <sup>+</sup> T <sub>TE</sub> cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc-IL-4 is indispensable for reinvigorating intratumoural CD8 <sup>+</sup> T <sub>TE</sub> 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.
Keywords
Animals, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Mice, Interleukin-4/metabolism, Interleukin-4/immunology, Female, TOR Serine-Threonine Kinases/metabolism, TOR Serine-Threonine Kinases/antagonists & inhibitors, Humans, Neoplasms/immunology, Neoplasms/therapy, STAT6 Transcription Factor/metabolism, Cell Line, Tumor, Immunoglobulin Fc Fragments/immunology, Recombinant Fusion Proteins/metabolism, Recombinant Fusion Proteins/therapeutic use, Male, Immune Checkpoint Inhibitors/pharmacology, Immune Checkpoint Inhibitors/therapeutic use, Mice, Inbred C57BL, Glycolysis/drug effects, Xenograft Model Antitumor Assays, Signal Transduction, Immunotherapy, Immunotherapy, Adoptive
Pubmed
Web of science
Open Access
Yes
Create date
30/09/2024 14:20
Last modification date
02/11/2024 7:10
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