RESUMO
BACKGROUND: The role of androgens and other sex steroids is known to influence the prognosis and progression of prostate cancer through different disease states. While androgens are generally regarded as immunosuppressive and estrogens as inflammatory, the specific influence of sex steroids on the immune microenvironment of prostate tumors remains incompletely understood. MATERIAL AND METHODS: In this study, we evaluate the link between sex steroids and prostate cancer immune cells, particularly macrophages. Using in vitro and in vivo models, as well as ex vivo culture of patient prostate tissue, we evaluated the influence of androgen, estrogen, and progesterone on immune cells of the prostate microenvironment. RESULTS: In vitro, we observed sex steroids induced indirect changes on prostate cancer cell proliferation via THP-1 derived macrophages, but no clear changes were induced using human monocyte derived macrophages. Comparing immunohistochemistry for immunosuppressive macrophage marker CD163 with concomitant circulating sex steroids from the same patients, we observed a correlation with higher dehydroepiandrosterone (DHEA)-sulfate and estrone-sulfate levels associated with higher prostate CD163 expression. Similar relationships between DHEA and CD163 levels were observed in ex vivo cultured prostate biopsies. Finally, in a murine prostate cancer model of long-term sex steroids we observed significant differences in tumor growth in mice implanted with estrogen and DHEA diffusion tubes. CONCLUSIONS: Our results highlight the complex influence of sex steroids on the immune cell composition of prostate tumors. Understanding this biology may help to further personalized therapy and improve patient outcomes.
RESUMO
Within the prostate tumor microenvironment (TME) there are complex multi-faceted and dynamic communication occurring between cancer cells and immune cells. Macrophages are key cells which infiltrate and surround tumor cells and are recognized to significantly contribute to tumor resistance and metastases. Our understanding of their function in the TME is commonly based on in vitro and in vivo models, with limited research to confirm these model observations in human prostates. Macrophage infiltration was evaluated within the TME of human prostates after 72 h culture of fresh biopsies samples in the presence of control or enzalutamide. In addition to immunohistochemistry, an optimized protocol for multi-parametric evaluation of cellular surface markers was developed using flow cytometry. Flow cytometry parameters were compared to clinicopathological features. Immunohistochemistry staining for 19 patients with paired samples suggested enzalutamide increased the expression of CD163 relative to CD68 staining. Techniques to validate these results using flow cytometry of dissociated biopsies after 72 h of culture are described. In a second cohort of patients with Gleason grade group ≥ 3 prostate cancer, global macrophage expression of CD163 was unchanged with enzalutamide treatment. However, exploratory analyses of our results using multi-parametric flow cytometry for multiple immunosuppressive macrophage markers suggest subgroup changes as well as novel associations between circulating biomarkers like the neutrophil to lymphocyte ratio (NLR) and immune cell phenotype composition in the prostate TME. Further, we observed an association between B7-H3 expressing tumor-associated macrophages and the presence of intraductal carcinoma. The use of flow cytometry to evaluate ex vivo cultured prostate biopsies fills an important gap in our ability to understand the immune cell composition of the prostate TME. Our results highlight novel associations for further investigation.