Protective role of testosterone in melanoma metastasis
Markman JL1*, Wakita D1, Crother TR1, Arditi M1
1Cedars Sinai Medical Center
Introduction: At advanced age, men have increasingly higher incidence in melanoma compared with women. With low survival rate for patients with distant metastasis, especially in men, studies aimed at elucidating the mechanisms underlying this gender disparity are warranted. The impact that testosterone (T) has on immune function in melanoma patients is currently unknown.
Methods: We used B16 and YUMM1.7 melanoma metastatic models in C57/Bl6 mice. YUMM1.7 cells were derived from a genetically engineered mouse with human mutations. To investigate the role of innate immunity, we depleted neutrophils or natural-killer (NK) cells. To investigate the role of T, castration surgeries were performed 4 weeks before B16 injection and T pellets were inserted at the time of surgery.
Results: Mice injected with melanoma cells revealed that females have higher lung tumor burden, reduced neutrophil infiltration, and decreased NK cell activation compared with males. Interestingly, castration studies revealed an increased tumor burden in the lungs of castrated male mice and worse survival compared with sham male mice, indicating a protective role for testosterone. Further, T replacement in castrated mice was able to rescue the increased tumor burden to levels seen in sham males. Ovariectomies had no effect. Neutrophil depletion increased tumor burden and reduced NK activation only in males, indicating a potential gender difference. A subsequent NK depletion study revealed significantly increased tumor burden in both male and female NK-depleted mice, but the gender difference was still apparent.
Conclusion: Our data indicates that both neutrophils and NK cells are important for the initial response against melanoma colonization of the lung. Neutrophil depletion and castration data indicate that there is a gender specific response of these cells, which may contribute to the gender disparity observed in human incidence and survival. Further, T replacement at physiological levels may benefit a subset of aging melanoma patients.