BERKELEY, CA (UroToday.com) - Prostate cancer (PCA) is the second leading cause of cancer-related death in men with a death rate reaching 26.7% for 2001-2005 in the United States.
A large body of literature based on histopathological, epidemiological, and molecular pathology data suggests that chronic inflammation might play an important role in prostate oncogenesis. To thoroughly evaluate the role of inflammation in PCA, it is critical to analyze molecular features and extent of inflammation in prostatic tissues with and without carcinoma. We found that the expression of a number of genes encoding pro-inflammatory and homeostatic cytokines, including IL-6, IL-7 and IL-15 is detectable more frequently, and to a higher extent, in PCA as compared to Benign Prostatic Hyperplasia (BPH) tissues. In addition, we have reported for the first time that IL-7 and IL-15 serum levels are significantly higher in patients with PCA than in patients with BPH. As expected, IL-6 titres were also significantly higher in patients with PCA than in patients with BPH.
Common γ-chain receptor cytokines are known to have a major impact on cytotoxic T cell development, proliferation, and survival.[5,6] However, a recent study indicates that IL-2, IL-7 and IL-15 may also induce the expression of the “exhaustion” marker programmed death receptor 1 (PD-1) and of its ligands, PD-L1 and PD-L2, in CD8+ T cells from healthy donors, even at moderate cytokine concentrations.In contrast, IL-21 has been shown to rescue exhausted T cells.[8-10] Notably PD-1 has been found to be expressed in CD8+ T cells infiltrating PCA. However, no data are currently available regarding BPH infiltrating lymphocytes.
These findings urged us to verify whether the expression of the genes encoding these cytokines in prostatic tissues from patients bearing PCA or BPH is associated with the activation of cytotoxic T cells or, in contrast, with their exhaustion. We therefore evaluated the expression of PD-1 in tissue infiltrating CD8+ T cells from each group.
Preliminary results suggest that PD-1 is equally expressed in high percentages of CD8+ T cells infiltrating either PCA or BPH consistent with an “exhausted” CD8+ T cell phenotype in prostate tissues. These data support previous reports on the phenotypic characteristics of circulating and tissue infiltrating lymphocytes in chronic viral infections.[12-15] In this context, it is remarkable that the expression of the IL-21 gene, that is of the gene encoding the cytokine preventing PD-1 mediated T cell exhaustion[8,10,16] is, in our hands, equally rarely detectable in BPH or PCA.
Taken together these data indicate that, although both BPH and PCA are infiltrated by exhausted PD1+ CD8+ T cells, consistent with a chronic stimulation, local gene expression and systemic secretion of a number of soluble inflammation mediators are significantly increased in PCA, as compared to BPH.
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Chantal Mengus, Clémentine le Magnen, Emanuele Trella, Kawa Yousef, Lukas Bubendorf, Maurizio Provenzano, Alexander Bachmann, Michael Heberer, Giulio C. Spagnoli and Stephen Wyler as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.