NOTCH1 drives sexually dimorphic immune responses in hepatocellular carcinoma

Hepatocellular carcinoma presents strong sexual dimorphism, being two to three 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 antitumor immunity and response to FDA-approved immunotherapies. Surprisingly, males harboring NOTCH1-driven tumors displayed enhanced antitumor 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 dendritic cell (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. Significance: Although HCC presents strong sexual dimorphism, the role of sex in response to immunotherapies remains elusive. With a novel HCC mouse model and validation in patients with HCC, we demonstrate that NOTCH1 disrupts antitumor immunity specifically in females through a mechanism mediated by sex chromosome genes, which is reversed with CD40 agonism. See related commentary by Zhu and Koltsova, p. 452.