Immunobiology of IL-17A in human colorectal cancer

Abstract

During the last decade tumor infiltration by immune cells has been recognized as a key factor determining clinical outcome. Whereas the presence within tumor tissues of defined lymphocytic populations, including cytotoxic CD8+ T cells and IFN-gamma-producing T-helper 1 cells has been univocally recognized to predict favorable prognosis, the clinical relevance and the pathophysiological role of IL-17-producing cells remain unclear. In some tumor types, including ovarian, prostate and lung cancer, a positive association between tumor infiltration by IL-17+ cells and prolonged patient survival has been reported. In contrast, in colorectal cancer (CRC), IL-17 expression has been shown to predict unfavorable clinical outcome and to weaken the beneficial effect of tumor infiltration by CD8+ T cells. However, restricted numbers of patients were analyzed and no functional data concerning the IL-17 source and the potential mechanisms underlying its negative effect were provided by these studies. In the enclosed work we have investigated prognostic significance, phenotype, and functional features of tumor-infiltrating IL-17-producing cells in human CRC. Upon analysis of a tissue micro-array (TMA) including 1400 cases of primary CRC, we found that tumor infiltration by IL-17+ cells was significantly associated with lower T (tumor border) and N (lymph nodes involvement) stage, but in contrast to previous findings, did not per se impact on overall patients survival. Interestingly, numbers of IL-17+ cells strongly correlated with those of CD8+ and CD16+ myeloperoxidase (MPO)+ neutrophils, which were predictive of better clinical outcome in the same patient cohort. Phenotypic analysis revealed that the majority of tumor infiltrating IL-17+ cells consisted of polyfunctional T helper 17 (Th17), producing, in addition to IL-17 a spectrum of pro-inflammatory cytokines and chemokines such as TNF-alpha??IL-21, IL-22, and GM-CSF, and, IFN-gamma? and IL-8. Interestingly, tumor-derived Th17 cells induced IL-8-dependent neutrophil migration and enhanced MPO release. Furthermore, tumor-derived Th17 cells favored the indirect recruitment of CD8+ T cells, by triggering chemokine release from tumor-associated endothelial cells. More surprisingly, CD8+ T cells were also directly recruited by Th17 cells in a CCL20 dependent manner. Importantly, the direct effect of Th17 proved sufficient to drive CD8+ T cells into an engineered CRC tissue-like structure. Our data suggest that CRC infiltrating Th17 cells can favor the recruitment of clinical relevant effector cells into the tumor site, therefore contributing to a more favorable clinical outcome. Altogether our findings unravel a positive role possibly played by tumor infiltrating polyfunctional Th17 cells in CRC and underline their pleiotropic effects beyond IL-17 production.