Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

International audienceUnlike most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Here, we show that inactivation of Znrf3 in the mouse adrenal cortex, recapitulating the most frequent alteration in ACC patients, is associated with sexually dimorphic tumour progression. Although female knockouts develop metastatic carcinomas at 18 months, adrenal hyperplasia regresses in male knockouts. This male-specific phenotype is associated with androgen-dependent induction of senescence, recruitment and differentiation of highly phagocytic macrophages that clear-out senescent cells. In contrast, in females, macrophage recruitment is delayed and dampened, which allows for aggressive tumour progression. Consistently, analysis of TCGA-ACC data shows that phagocytic macrophages are more prominent in men and associated with better prognosis. Altogether, these data show that phagocytic macrophages are key players in the sexual dimorphism of ACC that could be novel allies in the fight against this devastating cancer. Teaser: Androgen-dependent senescence induces recruitment of phagocytic macrophages, preventing adrenocortical carcinoma development