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Article: Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy

TitleChronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy
Authors
Issue Date1-Nov-2022
PublisherCell Press
Citation
Cell Reports, 2022, v. 41, n. 7 How to Cite?
Abstract

Identifying signals that govern the differentiation of tumor-infiltrating CD8+ T cells (CD8+ TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8+ T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8+ T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8+ TILs devoid of IFN-I signaling develop less exhaustion features, provide better tumor control, and show greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of Tex cells. Thus, cell-intrinsic IFN-I signaling regulates the extent of CD8+ TIL exhaustion and has important implications for immunotherapy.


Persistent Identifierhttp://hdl.handle.net/10722/328237
ISSN
2023 Impact Factor: 7.5
2023 SCImago Journal Rankings: 4.279

 

DC FieldValueLanguage
dc.contributor.authorChen, WX-
dc.contributor.authorTeo, JMN-
dc.contributor.authorYau, SW-
dc.contributor.authorWong, MYM-
dc.contributor.authorLok, CN-
dc.contributor.authorChe, CM-
dc.contributor.authorJaved, A-
dc.contributor.authorHuang, YH-
dc.contributor.authorMa, SPN-
dc.contributor.authorLing, GS-
dc.date.accessioned2023-06-28T04:39:57Z-
dc.date.available2023-06-28T04:39:57Z-
dc.date.issued2022-11-01-
dc.identifier.citationCell Reports, 2022, v. 41, n. 7-
dc.identifier.issn2211-1247-
dc.identifier.urihttp://hdl.handle.net/10722/328237-
dc.description.abstract<p>Identifying signals that govern the differentiation of tumor-infiltrating CD8<sup>+</sup> T cells (CD8<sup>+</sup> TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8<sup>+</sup> T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8<sup>+</sup> T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8<sup>+</sup> TILs devoid of IFN-I signaling develop less exhaustion features, provide better tumor control, and show greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of Tex cells. Thus, cell-intrinsic IFN-I signaling regulates the extent of CD8<sup>+</sup> TIL exhaustion and has important implications for immunotherapy.<br></p>-
dc.languageeng-
dc.publisherCell Press-
dc.relation.ispartofCell Reports-
dc.titleChronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy-
dc.typeArticle-
dc.identifier.doi10.1016/j.celrep.2022.111647-
dc.identifier.hkuros344955-
dc.identifier.volume41-
dc.identifier.issue7-
dc.identifier.issnl2211-1247-

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