Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development - Archive ouverte HAL Access content directly
Preprints, Working Papers, ... Year : 2022

Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

James Wilmouth
Julie Olabe
  • Function : Author
Diana Garcia-Garcia
  • Function : Author
Cécily Lucas
Rachel Guiton
  • Function : Author
Florence Roucher-Boulez
  • Function : Author
Damien Dufour
  • Function : Author
Christelle Damon-Soubeyrand
  • Function : Author
Isabelle Sahut-Barnola
  • Function : Author
Jean-Christophe Pointud
  • Function : Author
Yoan Renaud
Adrien Levasseur
  • Function : Author
Igor Tauveron
  • Function : Author
Pierre Val

Abstract

Summary In contrast with most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Homozygous deletion of the negative WNT pathway regulator ZNRF3 is the most frequent alteration in ACC patients. Here, we show that Cre-mediated inactivation of Znrf3 in steroidogenic cells of the mouse adrenal cortex is associated with sexually dimorphic tumour progression. Indeed, although most knockout female mice develop metastatic carcinomas over an 18 month-time course, adrenal hyperplasia gradually regresses in male knockout mice. This male-specific regression is associated with induction of senescence and recruitment of macrophages, which differentiate as active phagocytes that clear-out senescent preneoplastic cells. Macrophage recruitment is also observed in female mice. However, it is delayed and dampened compared to males, which allows for tumour progression. Interestingly, testosterone treatment of female knockouts is sufficient to induce senescence, recruitment of phagocytic macrophages and regression of hyperplasia. We further show that although macrophages are present within adrenal tumours at 18 months, MERTK high active phagocytes are mostly found in indolent lesions in males but not in aggressive tumours in females. Consistent with our observations in mice, analysis of RNA sequencing data from the TCGA cohort of ACC shows that phagocytic macrophages are more prominent in men than women and associated with better prognosis. Altogether, these data establish that phagocytic macrophages prevent aggressive ACC development in male mice and suggest that they may play a key role in the unusual sexual dimorphism of ACC in patients.

Dates and versions

hal-03765725 , version 1 (31-08-2022)

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James Wilmouth, Julie Olabe, Diana Garcia-Garcia, Cécily Lucas, Rachel Guiton, et al.. Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development. 2022. ⟨hal-03765725⟩
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