Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development

Author:

Wilmouth James J.1ORCID,Olabe Julie1ORCID,Garcia-Garcia Diana1,Lucas Cécily1,Guiton Rachel1ORCID,Roucher-Boulez Florence123ORCID,Dufour Damien1ORCID,Damon-Soubeyrand Christelle1,Sahut-Barnola Isabelle1ORCID,Pointud Jean-Christophe1,Renaud Yoan1ORCID,Levasseur Adrien1,Tauveron Igor14,Lefrançois-Martinez Anne-Marie1ORCID,Martinez Antoine1,Val Pierre1ORCID

Affiliation:

1. Institut GReD (Genetics, Reproduction and Development), CNRS UMR 6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France.

2. Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocriniennes, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

3. Université Claude Bernard Lyon 1, Lyon, France.

4. Endocrinologie Diabétologie CHU Clermont Ferrand, 58 rue Montalembert, F63000 Clermont-Ferrand, France.

Abstract

Unlike most cancers, adrenocortical carcinomas (ACCs) are more frequent in women than in 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 tumor 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 tumor progression. Consistently, analysis of TCGA-ACC data shows that phagocytic macrophages are more prominent in men and are associated with better prognosis. Together, these data show that phagocytic macrophages are key players in the sexual dimorphism of ACC that could be previously unidentified allies in the fight against this devastating cancer.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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