Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development

Area of Science:

• Oncology
• Immunology
• Endocrinology

Background:

• Adrenocortical carcinomas (ACC) exhibit a higher incidence in women compared to men.
• The biological mechanisms underlying this observed sexual dimorphism in ACC are not well understood.
• Genetic alterations in tumor suppressors, such as Zinc and Ring Finger 3 (Znrf3), are common in ACC.

Purpose of the Study:

• To investigate the role of Znrf3 inactivation in sexually dimorphic tumor progression in the adrenal cortex.
• To elucidate the mechanisms contributing to the observed sex-based differences in ACC development and regression.
• To identify potential therapeutic targets by understanding the immune microenvironment's role.

Main Methods:

• Utilized a mouse model with Znrf3 inactivation in the adrenal cortex to mimic human ACC alterations.
• Analyzed tumor progression and regression in both male and female knockout mice.
• Investigated the role of macrophages, senescence, and androgen signaling in the male-specific regression phenotype.
• Examined The Cancer Genome Atlas (TCGA) adrenocortical carcinoma data for correlations between macrophage presence and patient prognosis.

Main Results:

• Znrf3 inactivation led to metastatic carcinoma development in female mice but regression of adrenal hyperplasia in male mice.
• Male mice exhibited androgen-dependent induction of senescence and recruitment of highly phagocytic macrophages that cleared senescent cells.
• Female mice showed delayed and dampened macrophage recruitment, facilitating aggressive tumor progression.
• Analysis of TCGA-ACC data revealed a higher prevalence of phagocytic macrophages in males, correlating with better prognosis.

Conclusions:

• Phagocytic macrophages play a critical role in the sexual dimorphism of adrenocortical carcinoma progression.
• The male-specific clearance of senescent cells by macrophages offers a potential mechanism for tumor regression.
• Targeting macrophage function represents a promising, previously unrecognized therapeutic strategy for combating ACC in women.