Loss of testosterone impairs anti-tumor neutrophil function

Abstract

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. Methods We used B16 and YUMM melanoma lung metastatic models. Neutrophil depletion, castration, testosterone (T) replacement, and bone marrow transplant (BMT) were performed. Neutrophils from prostate cancer patients were analyzed. Data In castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Remarkably, replacement of T effectively normalized the tumor burden in castrated male mice. Neutrophil depletion increased tumor burden only in males, suggesting a sex difference in neutrophils. Sex BMT experiments showed that the hormonal microenvironment is crucial, not the sex of the immune cell. Further, a BMT from ARTfm mice with a truncated androgen receptor increased tumor burden and impacted neutrophil function towards a pro-tumor phenotype. Finally, 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. Conclusion Our data indicate that innate immunity is important for the response against melanoma colonization and suggest a sex specific response of neutrophils with impaired function in the absence of T. 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.