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
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
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