STUB1-CHIC2复合物抑制CD8 T细胞以抑制肿瘤免疫。

A STUB1-CHIC2 complex inhibits CD8 T cells to restrain tumor immunity.

作者信息

LaFleur Martin W, Milling Lauren E, Prathima Priyamvada, Li Vivian, Lemmen Ashlyn M, Streeter Ivy S L, Heisig Paul K S, Derosia Nicole M, Riffo Elizabeth, Xu Haonan, Nguyen Thao H, Kolengaden Aashiya, Markson Samuel C, Doench John G, Sharpe Arlene H

机构信息

Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

出版信息

Nat Immunol. 2025 Aug 12. doi: 10.1038/s41590-025-02231-6.

DOI:10.1038/s41590-025-02231-6

PMID:40796662

Abstract

In vivo CRISPR screens in CD8 T cells have previously uncovered targets for cancer immunotherapy; however, a minority of the genome has been individually annotated, suggesting that additional regulators remain to be discovered. Here we assessed 899 genes in CD8 T cells responding to murine melanoma and identified the E3 ubiquitin ligase STUB1 as a new negative regulator of anti-tumor CD8 T cell function. We demonstrated that Stub1 knockout CD8 T cells effectively control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate cytokine receptor expression in mouse and human CD8 T cells. Among the regulated cytokine receptors, interleukin-27 receptor α is essential for tumor growth control mediated by Stub1/Chic2 knockout CD8 T cells. Together, these findings establish the STUB1-CHIC2 complex as a regulator of cytokine receptor expression in CD8 T cells and provide rationale for inhibiting this pathway to enhance CD8 T cell-mediated anti-tumor immunity.

摘要

此前，在CD8 T细胞中进行的体内CRISPR筛选已发现癌症免疫治疗的靶点；然而，只有少数基因组得到了单独注释，这表明仍有其他调节因子有待发现。在这里，我们评估了对小鼠黑色素瘤产生反应的CD8 T细胞中的899个基因，并确定E3泛素连接酶STUB1是抗肿瘤CD8 T细胞功能的一个新的负调节因子。我们证明，敲除Stub1的CD8 T细胞能在多种小鼠模型中有效控制肿瘤生长。从机制上讲，STUB1与衔接蛋白CHIC2相互作用，以调节小鼠和人类CD8 T细胞中的细胞因子受体表达。在受调节的细胞因子受体中，白细胞介素-27受体α对于敲除Stub1/Chic2的CD8 T细胞介导的肿瘤生长控制至关重要。总之，这些发现确立了STUB1-CHIC2复合物作为CD8 T细胞中细胞因子受体表达的调节因子，并为抑制该途径以增强CD8 T细胞介导的抗肿瘤免疫提供了理论依据。