肿瘤微环境
细胞毒性T细胞
免疫监视
癌症研究
白细胞介素15
生物
癌症免疫疗法
免疫系统
白细胞介素12
免疫疗法
免疫学
CD8型
自然杀伤细胞
细胞因子
白细胞介素
体外
生物化学
作者
Fernando Souza-Fonseca-Guimarães,Gustavo Rodrigues Rossi,Laura F. Dagley,Momeneh Foroutan,Timothy R. McCulloch,Jumana Yousef,Hae-Young Park,Jennifer H. Gunter,Paul A. Beavis,Chii-Wann Lin,Soroor Hediyeh-Zadeh,Tania Camilleri,Melissa J. Davis,Nicholas D. Huntington
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2022-06-27
卷期号:10 (9): 1047-1054
被引量:8
标识
DOI:10.1158/2326-6066.cir-21-1052
摘要
Antibodies targeting "immune checkpoints" have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8+ T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK-cell antitumor function is dependent on the cytokine IL15. Ablation of the IL15 signaling inhibitor CIS (Cish) enhances NK-cell antitumor immunity by increasing NK-cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK-cell fitness via the production of immunosuppressive transforming growth factor β (TGFβ), a suppression which occurs even in the presence of high IL15 signaling. Here, we identified an unexpected interaction between CIS and the TGFβ signaling pathway in NK cells. Independently, Cish- and Tgfbr2-deficient NK cells are both hyperresponsive to IL15 and hyporesponsive to TGFβ, with dramatically enhanced antitumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anticancer immunity.
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