NOTCH1 drives sexually dimorphic immune responses in hepatocellular carcinoma.

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2024-11-19 DOI:10.1158/2159-8290.CD-24-1215

Katherine E Lindblad, Romain Donne, Ian Liebling, Marina Barcena-Varela, Anthony Lozano, Marina Ruiz de Galarreta, Maxime Dhainaut, Nesteene J Param, Bruno Giotti, Sarah Cappuyns, Takahiro Kodama, Yulei Wang, Alice O Kamphorst, Alexander M Tsankov, Amaia Lujambio

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Abstract

Hepatocellular carcinoma presents strong sexual dimorphism, being 2-3 times more frequent in males than in females; however, the role of sex in response to immunotherapies in HCC remains unknown. We demonstrate that NOTCH1, an understudied oncogene in HCC, elicits sexually dimorphic anti-tumor immunity and response to FDA-approved immunotherapies. Surprisingly, males harboring NOTCH1-driven tumors displayed enhanced anti-tumor immune responses, which, in mice, were mediated by dendritic and T cells. Conversely, females harboring NOTCH1-driven tumors presented immune evasion and resistance to immunotherapies through a defect in DC-mediated priming and activation of CD8+ T cells in mice, which was restored therapeutically with CD40 agonism. Mechanistically, the sexually dimorphic immunity was mediated by genes in the sex chromosomes but not by sex hormones. Together, our study unravels an unexpected association between NOTCH1 and sex in cancer immunity and highlights the potential of restoring the DC-CD8+ T cell axis with CD40 agonism to improve outcomes.

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NOTCH1驱动肝细胞癌的性别双态免疫反应

肝细胞癌具有很强的性别二形性，男性发病率是女性的 2-3 倍；然而，性别在肝细胞癌免疫疗法反应中的作用仍然未知。我们证明，NOTCH1是一种在HCC中未被充分研究的癌基因，它能激发性别双态的抗肿瘤免疫和对FDA批准的免疫疗法的反应。令人惊讶的是，携带NOTCH1驱动肿瘤的雄性动物显示出更强的抗肿瘤免疫反应，在小鼠体内，这种反应是由树突状细胞和T细胞介导的。相反，携带NOTCH1驱动肿瘤的雌性则通过DC介导的小鼠CD8+ T细胞引物和活化缺陷表现出免疫逃避和对免疫疗法的抗性，CD40激动剂可恢复这种抗性。从机理上讲，性二态免疫是由性染色体上的基因介导的，而不是由性激素介导的。总之，我们的研究揭示了癌症免疫中NOTCH1与性别之间意想不到的联系，并强调了通过CD40激动剂恢复DC-CD8+ T细胞轴以改善预后的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.