We sought to investigate the nature and timing of the prostate-infiltrating T-cell response that has been demonstrated by many investigator groups to occur following castration. We found that in the Lewis rat there is a relative increase of CD8+ T cells into the prostate by 30 days post castration, and this response decreases over time. Similarly, CD4+ and CD8+ infiltrating T cells at this time demonstrated a TH1 phenotype. A TH17 response was also observed by day 30, and this persisted for at least 90 days post castration, when fewer CD8+ T cells and TH1-associated responses were observed. While TH1 responses were observed systemically following castration, the TH17 response was only observed in the prostate. We then demonstrated that PIL from rats localized to androgen-deprived prostate tissue at an increased frequency relative to PIL transferred to sham control rats, suggesting that castration alters prostate tissue making it more amenable to T-cell infiltration. Our data are consequently the first to demonstrate that castration promotes a time-dependent prostate-localized TH1 response and a chronic TH17 response.
We observed an increase in the frequency of infiltrating CD8+ cells relative to CD4+ cells by 30 days post castration, and further identified that the prostate T cells upregulated expression of TH
1 cytokines (IFNγ and TNFα) at this same time, consistent with an inflammatory, cytolytic-type immune response. The frequency, localization, and TH
bias of tumor-infiltrating lymphocytes (TILs), in patients with colon and lung cancer, have been reported to be predictive of prognosis (26
). Similarly, primary prostate tumors with gene expression profiles demonstrating increased TH
1-biased genes are associated with a better prognosis (27
). However, in our study the CD8+ T-cell infiltration and TH
1 bias we observed was diminished by 90 days post castration. While we don’t understand the mechanism by which these cells declined in frequency, and similar time-dependent studies have not been conducted in patients with prostate cancer following treatment with androgen deprivation to our knowledge, it is interesting to speculate that strategies to prolong the duration of TH
1-type cytolytic T-cell responses following castration might be exploited as a prostate cancer treatment.
The role of TH
17 cells in tumor development and progression remains controversial (28
). Correlations linking a TH
17 bias both with tumor promotion and suppression have been reported in prostate cancer patients. In one study, an increased frequency of TH
17 cells in patient PBMC was significantly associated with a shorter time to metastatic progression (29
). In a separate study, a high frequency of TH
17-expressing PIL in prostate cancer patients was associated with a lower pathologic Gleason score (30
). It should be noted that both of these studies were relatively small, and larger studies may be needed to address the association of TH
17 bias with disease outcome, and whether the difference is due to the local or systemic response. TH
17 PILs may be responding specifically to tumor tissue, whereas the TH
17 cells in the periphery may be more indicative of global inflammation. Interestingly, STAT3 activation is necessary for the development of the TH
17 phenotype, and has been shown to be active following castration (31
). Inhibition of activated STAT3 significantly slowed prostate tumor growth following castration in mice (32
). Functional analysis of the TH
17 cells in normal and tumor-bearing prostates will be needed to demonstrate their role affecting other immune cells and their association with prostate cancer regression or recurrence. Similarly, tumor-bearing animal models may be useful to determine whether TH
17 immunity persists or wanes with the emergence of castrate-resistant disease.
Finally, we show in our study that PILs from Lewis rats localized to androgen-deprived prostates at an increased frequency compared with sham controls. Theses results suggest that castration alters the prostate tissue environment to enable T-cell localization. This may be due to destruction of prostate cells with increased presentation of T-cell antigens, due to disruption of vasculature enabling T-cell trafficking, due to effects on chemokine expression, or potentially due to effects on other prostate tissue populations permitting T-cell localization and retention. Specifically, it has been demonstrated in human tissues that androgen deprivation increases prostate epithelial gene expression of the chemoattractant IP-10/CXCL10, suggesting this might increase T-cell trafficking and retention (33
). While these observations do not exclude the possibility that castration may directly affect the phenotype and repertoire of T cells able to infiltrate the prostate, this does not appear to be the predominant reason, since PIL from either castrate- or sham-treated animals were able to similarly infiltrate castrate-treated prostate tissues. In any case, our findings show that castration temporarily leads to a TH
1-type T-cell infiltration of the prostate. This response, and the timing of this response, might be combined with other immune-based therapies to prolong or increase the presence and activity of cytolytic T cells within prostate tumors as a treatment for prostate cancer.