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.

中文翻译：

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NOTCH1 驱动肝细胞癌的性二态性免疫反应


肝细胞癌表现出强烈的性二态性，男性的发病率是女性的 2-3 倍;然而，性别对 HCC 免疫疗法的反应作用仍然未知。我们证明 NOTCH1 是 HCC 中一种研究不足的癌基因，可引发性二态性抗肿瘤免疫和对 FDA 批准的免疫疗法的反应。令人惊讶的是，携带 NOTCH1 驱动肿瘤的雄性表现出增强的抗肿瘤免疫反应，这在小鼠中是由树突状细胞和 T 细胞介导的。相反，携带 NOTCH1 驱动肿瘤的雌性通过 DC 介导的小鼠 CD8+ T 细胞启动和激活缺陷表现出免疫逃避和对免疫疗法的耐药性，这种缺陷通过 CD40 激动作用在治疗中恢复。从机制上讲，性二态免疫是由性染色体中的基因介导的，而不是由性激素介导的。总之，我们的研究揭示了 NOTCH1 与癌症免疫中性别之间的意想不到的关联，并强调了通过 CD40 激动作用恢复 DC-CD8+ T 细胞轴以改善结果的潜力。