Pro-tumorigenic roles for CCL20, CCR6, IL-23 and Th17 cells in human prostate cancer

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Human prostate cancer, which ranks second among cancers as a cause of death in the western male population, is a malignancy that has been postulated to arise from precancerous processes associated with inflammation. Chemokines, a family of chemotactic cytokines, may contribute to cancer formation by mediating leukocyte recruitment to sites of developing or established cancer. In a screen for chemokine expression by normal prostate epithelial cells, CCL20 was the most abundant. CCL20 is the only known chemokine ligand for the receptor CCR6. Recent studies have shown that CCR6 is expressed on all human Th17 cells (IL-17-secreting CD4+ T cells), and that activated Th17 cells also produce high levels of CCL20. Th17 cells have been implicated in tumor growth based on the tumor-promoting activity of IL-23, a principal growth factor for Th17 cells. We hypothesized that CCL20 expressed on prostate epithelium may recruit CCR6+ Th17 cells to inflamed prostate tissue, thereby contributing to the progression of prostate cancer. Immunohistochemistry showed that T and B cells comprise the majority of the inflammatory cells in the prostate. Immunofluorescence showed that both the T and B cells express high levels of CCR6, CCL20 and IL-17 and, surprisingly, we found that the prostate cancer cells themselves, when adjacent to inflammation, stained prominently for CCR6, CCL20, IL-17 and IL-23. In related experiments, we found that CCL20 was able to induce the proliferation of prostate cancer cells expressing CCR6. Analysis of a 40-specimen prostate cancer array supported the relationship between expression of CCL20 and cancer-associated inflammation by showing an inverse correlation between signals for CCL20 and alpha smooth muscle actin in stroma (p=0.04). Loss of alpha smooth muscle actin is characteristic of “reactive stroma” resulting from prior inflammation. Analysis of these arrays also showed a significant correlation between IL-23 expression and high-stage prostate cancer (p<0.05 for expression of IL-23 in Stage IV vs. Stage II) and between CCL20 expression and both high-stage (p<0.05 for expression of CCL20 in Stage IV vs. Stage II) and high-grade (p=0.02 for expression of CCL20 in cases with Gleason scores 8-10 vs. 6-7) prostate cancer. Taken together, our data suggest that IL-17, CCL20 and CCR6, each of which are expressed by both inflammatory cells and cancer cells may be components of inter-related paracrine and autocrine positive feedback loops involving cancer cells and inflammatory cells. CCL20 enhances tumor growth directly through CCR6-mediated proliferation and indirectly through enhanced recruitment of inflammatory cells such as Th17 cells. In addition, expression of IL-23 on cancer cells may induce expansion and activation of Th17 cells at the cancer site, enhancing inflammation and tumor progression.