Loss of MyD88 leads to more aggressive TRAMP prostate cancer and influences tumor infiltrating lymphocytes

BACKGROUND The influence of pattern recognition receptor (PRR) signaling in the prostate tumor microenvironment remains unclear. Although there may be a role for PRR agonists as adjuvants to therapy, prior evidence suggests tumor promoting as well as tumor inhibiting mechanisms. The purpose of this study is to examine the role of the key Toll-like receptor (TLR) signaling adaptor protein myeloid differentiation primary response gene 88 (MyD88) in prostate cancer development. METHODS MyD88-/- mice in a C57Bl6 background were crossed with transgenic adenocarcinomas of the mouse prostate (TRAMP) mice to create MyD88-/- TRAMPTg+/− animals, which were compared to MyD88+/+ TRAMPTg+/− animals and their non-transgenic counterparts at 30 weeks. Prostates were examined histologically, by immunohistochemistry and immunofluorescence staining, and by qPCR, to characterize tumor-infiltrating immune populations as well as activation of the downstream NF-κB pathway and androgen receptor (AR) expression. Splenocytes were examined for development of distinct immune cell populations. RESULTS Absence of MyD88 led to increased prostatic intraepithelial neoplasm (PIN) and areas of well-differentiated adenocarcinoma in TRAMP transgenic mice. Analysis of infiltrating immune populations revealed an increase in CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs), as evidenced by increased expression of prostatic arginase-1 and iNOS as well as the cytokine IL-10, and a deficiency in NK cells in prostates from MyD88-/- TRAMPTg+/− compared to MyD88+/+ TRAMPTg+/− mice, whereas a decrease in splenocytic NK cell differentiation was observed in MyD88-/- mice. Prostate tumors revealed no significant differences in NF-κB or AR expression in MyD88+/+ TRAMPTg+/− compared to MyD88-/- TRAMPTg+/− mice. CONCLUSIONS During prostate cancer development in the TRAMP model, MyD88 may play a role in limiting prostate tumorigenesis by altering tumor-infiltrating immune populations. This suggests that in the context of specific cancers, distinct PRRs and signaling pathways of innate immune signaling may influence the tumor microenvironment and represent a novel therapeutic strategy. Prostate 75: 463–473, 2015. © 2015 Wiley Periodicals, Inc.