Loss of testosterone impairs anti-tumor neutrophil function

Janet L Markman,Michael Luu,Magali Noval Rivas,Daiko Wakita,Malcolm E Lane,Edwin M Posadas,Daisy Martinon,Timothy R Crother,Moshe Arditi,Rebecca A Porritt

doi:10.1038/s41467-020-15397-4

Abstract

In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.

Highlights

In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male
In a retrospective study analyzing metastatic patterns from patients treated at a single center in Germany, females had a higher incidence of locoregional metastasis and a lower risk for distance metastasis (67.3% in females compared with 73.8% in males)[7]
This increased tumor burden occurred throughout the lung and on the surface, as confirmed by melanin content quantification and lung hematoxylin and eosin (H&E) staining (Supplementary Fig. 1a–b)

Summary

Introduction

The incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. We show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. The aberrant neutrophil phenotype was observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies. We observe that prostate cancer (PCa) patients undergoing androgen deprivation therapy exhibit impairments in neutrophil maturation and function. Taken together, these data illuminate the role of androgen signaling in neutrophil function, and the potential impact of this effect on cancer progression

Methods

Results

Conclusion