Abstract 1459: Revealing the underlying causes of the gender disparity in melanoma: Role of testosterone
Authors: Markman Janet , Wakita Daiko , Crother Timothy , Arditi Moshe 
Published: July 2016

Abstract
Introduction: At advanced age, men have increasingly higher incidence of melanoma compared with women, as well as continuously decreasing levels of testosterone. With the low rate of survival for distant metastatic patients with melanoma, especially in men, studies aimed at elucidating the immunological and hormonal mechanisms underlying the gender disparity are warranted.
Procedures: To investigate the gender disparity observed between men and women affected by melanoma, we used an experimental murine model where B16 melanoma cells were injected i.v. into C57BL/6 mice and lung colonization was assessed at day 14. The roles of neutrophils and NK cells were then investigated by specific cell depletion using anti-Ly6G(1A8) and anti-NK1.1 monoclonal antibodies, respectively. Depleting antibodies or control IgG were injected every 3 days, starting one day before melanoma cell injection. To elucidate the role of hormones, ovariectomy or castration surgeries were performed 4 weeks before B16 injection and 60 day slow release pellets were inserted at the time of surgery. Findings were reproduced with a second murine melanoma cell line (YUMM1.7) derived from a genetically engineered mouse harboring human mutations in BrafV600, as well as loss of Cdkn2a and PTEN.
Data: Compared with males, naïve female mice injected with melanoma (B16 or YUMM1.7) cells have higher lung tumor burden, reduced neutrophil infiltration, and decreased NK cell activation. Ovariectomy of female mice did not affect lung tumor burden, indicating that estrogen and progesterone are not protective. Interestingly, castrated males revealed increased lung metastasis and worse survival rates compared with sham male mice, suggesting a protective role for testosterone. Further, testosterone replacement in castrated mice significantly reduced the elevated lung tumor burden to equal levels observed in sham males. Depletion of NK cells greatly increased tumor burden in both male and female mice in a gender independent manner. In contrast, neutrophil depletion increased lung tumor burden only in male mice and had no significant affect in female mice, indicating a potential gender difference in neutrophils. Moreover, neutrophil depletion in male mice also reduced NK activation and IFN-γ production, suggesting a stimulatory relationship between neutrophils and NK cells.
Conclusion: Our data indicates that both neutrophils and NK cells are important for the initial response against melanoma colonization of the lung. Neutrophil depletion, as well as our castration data, indicate that there is a gender specific differential response, which may contribute to the gender disparity seen in human melanoma incidence and survival. Further, testosterone replacement at physiological levels may benefit a subset of melanoma patients.
Citation Format: Janet Markman, Daiko Wakita, Timothy Crother, Moshe Arditi. Revealing the underlying causes of the gender disparity in melanoma: Role of testosterone. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1459.