Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1

Ribonuclease 1 Induces T‐Cell Dysfunction and Impairs CD8+ T‐Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1

Abstract T‐cell‐based immunotherapy holds promise for eliminating cancer through T‐cell activation. However, prolonged interaction between T cells and tumors and the presence of immunosuppressive factors can diminish T‐cell cytotoxicity, leading to treatment failure. Here, ribonuclease 1 (RNase1), w...

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Main Authors: Wen‐Hao Yang, Bao‐Yue Huang, Hsing‐Yu Rao, Peng Ye, Bi Chen, Hao‐Ching Wang, Chih‐Hung Chung, Heng‐Hsiung Wu, Hung‐Rong Yen, Shao‐Chun Wang, Jong‐Ho Cha, Xiuwen Yan, Muh‐Hwa Yang, Mien‐Chie Hung
Format: Article
Language:English
Published: Wiley 2025-04-01
Series:Advanced Science
Subjects:
effector cytokine
immune checkpoint protein
ribonuclease 1
STAT1
T‐cell dysfunction
Online Access:https://doi.org/10.1002/advs.202404961
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Summary:Abstract T‐cell‐based immunotherapy holds promise for eliminating cancer through T‐cell activation. However, prolonged interaction between T cells and tumors and the presence of immunosuppressive factors can diminish T‐cell cytotoxicity, leading to treatment failure. Here, ribonuclease 1 (RNase1), which degrades RNA, reduced the expression of effector cytokines and increases immune checkpoint protein levels, inducing T‐cell dysfunction. RNase1 expression is positively associated with exhausted T‐cell gene signatures and immune checkpoint proteins across several cancer types. Cancer cells expressing RNase1 are resistant to CD8+ T‐cell‐mediated killing. RNase1 promotes tumor growth in immunocompetent, but not in immunodeficient, mouse models and inhibits CD8+ T‐cell activity in vivo. Mechanistically, RNase1 enters T cells and deactivates signal transducer and activator of transcription 1 (STAT1), causing T‐cell dysfunction. Loss of RNase1‐STAT1 interaction restores CD8+ T‐cell cytotoxicity. Notably, a study has found RNase1 might activate CD4+ T cells to inhibit breast cancer growth, while another has indicated it causes immunosuppression in liver cancer. The current research shows that RNase1 does not impact CD4+ T cells in vivo. Overall, the study supports the immunosuppressive role of RNase1 in cancer of negatively regulating STAT1 to impair CD8+ T‐cell cytotoxicity. Targeting the RNase1‐STAT1 interaction could prevent CD8+ T‐cell dysfunction in RNase1‐highly expressing cancer patients.
ISSN:2198-3844

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