**6. Macrophages**

Macrophages, one of the most abundant types of immune cells in tumor microenvironments, change the phenotype to promote tumor growth and metastasis. Macrophages are divided into classic macrophages (M1) and alternative macrophages (M2). M1 macrophages act in microbicidal and tumoricidal activity, and M2 macrophages act in tissue remodeling, immune tolerance, and tumor progression [39]. M1 macrophages are characterized by the secretion of interleukin-1β (IL-1β), IL-6, IL-12, and TNFα, whereas M2 macrophages are characterized by the secretion of IL-4, IL-10, and TGF-β. At early stages of tumor development, macrophages undergo classic activation and exhibit an M1 phenotype [36,40]. Cytokines secreted from M1 macrophages play roles in tumor initiation and early promotion [36]. Exposure of macrophages to IL-4, colony-stimulating factor-1 (CSF1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and TGFβ secreted by cancer cells polarize macrophages to the M2 phenotype, which acts to induce immunosuppressive microenvironments. Inflammatory cytokines secreted from adipocytes, such as TNFα, IL-6, IL1β, and CCL2, recruit macrophages to the adipose tissues. Diet-induced obesity leads to a shift of the macrophage phenotype from M2 to M1 in mice [41,42]. In contrast, in mammary adipose tissue of breast cancer in obese women, macrophages showed a decrease in the expression of IL-10 and CD11c, which are characteristic of an M1 polarization phenotype. However, they also showed an increase in the expression of CD206, which is a surface marker of the M2 polarization phenotype, suggesting a mixed polarization phenotype in tumor microenvironments [39,43]. Macrophages are known to promote cancer growth and metastasis in prostate cancer, but the association of macrophages with obesity in prostate cancer is still unclear. Different from breast cancer, adipocytes are located in the area surrounding the prostate and are not found within the prostate tissues. Prostate cancer and stromal cells secrete CCL2, which strongly recruits macrophages [44,45]. CCL2 levels were increased in the sera of HFD-fed mice with an LNCaP xenograft. It is also reported that the number of tumor-infiltrating macrophages is not associated with BMI [46]. The role of macrophages in prostate cancer with a background of obesity will require further study.

### **7. Myeloid-Derived Suppressor Cells (MDSCs)**

MDSCs have a strong immunosuppressive function that enables the regulation of immune response and suppresses overt inflammatory responses [47]. MDSCs represent a non-lymphoid immune suppressor cell population of myeloid origin that is enriched in cancer [48]. MDSCs are a heterogeneous population and express a mixture of surface markers typical for myeloid cells, but they lack the markers of lymphocytes, natural killer cells, macrophages, and dendritic cells [47]. MDSCs were originally found in mice, and their counterparts in humans are not well defined. MDSCs in mice are characterized by the surface marker Gr-1+CD11b+. MDSCs are divided into two major groups: cells with a morphology and surface markers characteristic of monocytes (monocytic (M)-MDSCs) and cells with surface markers characteristic of polymorphonuclear (PMN)-MDSCs). In mice, M-MDSCs are characterized by the surface markers of CD11b+Ly6Chigh Ly6G–, and PMN-MDSCs are characterized by CD11b+Ly6Clow Ly6G+. In humans, the equivalent cells to PMN-MDSCs are defined as CD11b+CD14–CD15+ or CD11b+CD14–CD66b+ and M-MDSCs as CD11b+CD14+HLA-DR–/low CD15 [49]. MDSCs are characterized by the suppression of T cell response by ARG1, iNOS, and reactive oxygen species. MDSCs inhibit T cells via arginase-1, iNOS, and ROS and induce regulatory T cells by IL-10 and TGF-β. MDSCs also modulate the cytokine production of macrophages and promote tumor angiogenesis and eventually metastasis [47]. In a prostate cancer mouse model (TRAMP mouse), IL-23 secreted from MDSCs can activate the androgen receptor pathway and promote cell survival and proliferation under an androgen-deprived condition. Blockade of IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer [50]. CXCL5 secreted from prostate cancer cells attracts MDSCs expressing CXCR2 in a mouse model of prostate cancer. Elimination of MDSCs or the blocking of CXCL5-CXCR2 signaling elicits an antitumor response for prostate cancer [51]. In humans, CD14+HLA-DR–/low M-MDSCs and Treg were significantly increased in peripheral blood from patients with prostate cancer compared with healthy donors. High levels of M-MDSCs in the blood were associated with a shorter median overall survival [52]. In patients with prostate cancer, MDSCs accumulate in the blood as prostate cancer progresses and inhibit the proliferation of autologous CD8+ T cells and the production of interferon-γ (IFN-γ) and granzyme-B [53]. MDSCs could be a new target in the prevention and treatment of prostate cancer and/or castration-resistant prostate cancer.
