小柯机器人

加拿大麦吉尔大学William J. Muller课题组发现，肿瘤来源的细胞因子Chi3l1可诱导中性粒细胞胞外陷阱，从而促进三阴性乳腺癌中T细胞的排斥。相关论文于2023年11月30日在线发表于国际学术期刊《免疫》。

研究人员表示，在三阴性乳腺癌（TNBC）中，CD8⁺ T细胞的基质限制与不良临床预后和对免疫检查点阻断（ICB）缺乏反应有关。

为了确定T细胞基质限制的介质，研究人员对缺乏转录因子Stat3的小鼠乳腺肿瘤进行了分析。在 Stat3^-/-肿瘤中，细胞因子Chi3l1的表达量减少。在人类TNBC和其他表现出T细胞基质限制的实体瘤中，Chi3l1的表达升高。在PyMT（polyoma virus middle T）乳腺癌模型中去除Chi3l1可产生抗肿瘤免疫反应并延迟乳腺肿瘤的发生。这些效应与T细胞肿瘤浸润增加和对ICB的反应改善有关。

从机理上讲，Chi3l1促进了中性粒细胞的募集和中性粒细胞胞外陷阱的形成，从而阻止了T细胞的浸润。这些研究结果让人们深入了解了基质限制CD8⁺ T细胞的机制，并表明以Chi3l1为靶点可促进各种肿瘤类型的抗肿瘤免疫。

附：英文原文

Title: The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer

Author: Tarek Taifour, Sherif Samer Attalla, Dongmei Zuo, Yu Gu, Virginie Sanguin-Gendreau, Hailey Proud, Emilie Solymoss, Tung Bui, Hellen Kuasne, Vasilios Papavasiliou, Chun Geun Lee, Suchitra Kamle, Peter M. Siegel, Jack A. Elias, Morag Park, William J. Muller

Issue&Volume: 2023-11-30

Abstract: In triple-negative breast cancer (TNBC), stromal restriction of CD8+ T cells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint blockade (ICB). To identify mediators of T cell stromal restriction, we profiled murine breast tumors lacking the transcription factor Stat3, which is commonly hyperactive in breast cancers and promotes an immunosuppressive tumor microenvironment. Expression of the cytokine Chi3l1 was decreased in Stat3/ tumors. CHI3L1 expression was elevated in human TNBCs and other solid tumors exhibiting T cell stromal restriction. Chi3l1 ablation in the polyoma virus middle T (PyMT) breast cancer model generated an anti-tumor immune response and delayed mammary tumor onset. These effects were associated with increased T cell tumor infiltration and improved response to ICB. Mechanistically, Chi3l1 promoted neutrophil recruitment and neutrophil extracellular trap formation, which blocked T cell infiltration. Our findings provide insight into the mechanism underlying stromal restriction of CD8+ T cells and suggest that targeting Chi3l1 may promote anti-tumor immunity in various tumor types.

DOI: 10.1016/j.immuni.2023.11.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00483-1

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