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BackgroundThe immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated.ObjectiveTo investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells.MethodsIL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments.ResultsIL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival.ConclusionsOur study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.

H-thymidine incorporation. Expression of cytokine genes in colorectal cancer and autologous healthy mucosa was tested by quantitative, real-time PCR. A tumor microarray (TMA) including >1,200 colorectal cancer specimens was stained with GM-CSF-and M-CSF-specific antibodies. Clinicopathological features and overall survival were analyzed.Results: GM-CSF induced CD16 expression in 66% AE 8% of monocytes, as compared with 28% AE 1% in cells stimulated by M-CSF (P ¼ 0.011). GM-CSF but not M-CSF-stimulated macrophages significantly (P < 0.02) inhibited colorectal cancer cell proliferation. GM-CSF gene was expressed to significantly (n ¼ 45, P < 0.0001) higher extents in colorectal cancer than in healthy mucosa, whereas M-CSF gene expression was similar in healthy mucosa and colorectal cancer. Accordingly, IL1b and IL23 genes, typically expressed by M1 macrophages, were expressed to significantly (P < 0.001) higher extents in colorectal cancer than in healthy mucosa. TMA staining revealed that GM-CSF production by tumor cells is associated with lower T stage (P ¼ 0.02), "pushing" growth pattern (P ¼ 0.004) and significantly (P ¼ 0.0002) longer survival in mismatch-repair proficient colorectal cancer. Favorable prognostic effect of GM-CSF production by colorectal cancer cells was confirmed by multivariate analysis and was independent from CD16 þ and CD8 þ cell colorectal cancer infiltration. M-CSF expression had no significant prognostic relevance. Conclusions: GM-CSF production by tumor cells is an independent favorable prognostic factor in colorectal cancer. Clin Cancer Res; 20(12); 3094-106. Ó2014 AACR.