MeansSD are depicted. helper WIKI4 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived WIKI4 Th17 brought on 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. Conclusions Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 Mouse monoclonal to CD33.CT65 reacts with CD33 andtigen, a 67 kDa type I transmembrane glycoprotein present on myeloid progenitors, monocytes andgranulocytes. CD33 is absent on lymphocytes, platelets, erythrocytes, hematopoietic stem cells and non-hematopoietic cystem. CD33 antigen can function as a sialic acid-dependent cell adhesion molecule and involved in negative selection of human self-regenerating hemetopoietic stem cells. This clone is cross reactive with non-human primate * Diagnosis of acute myelogenousnleukemia. Negative selection for human self-regenerating hematopoietic stem cells targeted treatments. strong class=”kwd-title” Keywords: COLORECTAL CANCER, T LYMPHOCYTES, CANCER IMMUNOBIOLOGY, IMMUNE RESPONSE, INFLAMMATORY MEDIATORS Significance of this study What is already known on this subject? Infiltration of colorectal cancers (CRCs) by defined populations of immune cells predicts clinical outcome irrespective of tumour stage. CRC-infiltrating CD8+ T cells and CD16+ myeloperoxidase (MPO)+ neutrophils have been found to be associated with prolonged survival, whereas infiltration by interleukin (IL)-17-producing cells, as evaluated in a limited number of cases, has been suggested to correlate with more severe prognosis. IL-17 is usually a proinflammatory cytokine mediating protumorigenic and proangiogenic effects. Monoclonal antibodies targeting IL-17/IL-17-receptor or impairing expansion of IL-17-producing cells may represent a new therapeutic option in CRC. What are the new findings? Analysis of a large cohort of CRCs shows that tumour-infiltrating IL-17-producing cells are not themselves predictive of poor clinical outcome. Intraepithelial localisation of CRC-infiltrating IL-17+ cells is usually associated with improved survival. CRC infiltration by IL-17+ cells correlates with the presence of beneficial CD8+ T cells and CD16+ MPO+ neutrophils. CRC-infiltrating IL-17+ cells, mostly consisting of polyfunctional T helper 17 cells (Th17), can recruit highly cytotoxic CD8+ T cells into tumour nests through CCL5 and CCL20 release. How might it impact on clinical practice in the foreseeable future? By disclosing the dual role played by CRC-Th17, our findings question therapeutic approaches aimed at inhibiting Th17 development or expansion, possibly resulting in impaired tumour infiltration by beneficial effector cells. The positive contribution of Th17 to anti-tumour immune responses should not be disregarded when developing new IL-17/Th17 targeted treatments in CRC. Introduction The tumour immune contexturethat is usually, type, location, density and functional orientation of tumour-infiltrating immune cells,1 predicts clinical outcome in human colorectal cancer (CRC). In particular, CD45RO+ memory T lymphocytes, cytotoxic CD8+ T cells (CTLs) and interferon (IFN)–producing T helper 1 cells (Th1) have been found to be associated with prolonged survival, irrespective of tumour stage (5C7). Unexpectedly, Foxp3+ regulatory T WIKI4 cells (Tregs),2 3 CD16+ and myeloperoxidase (MPO)+ myeloid cells,4C6 also correlate with favourable clinical outcome. In contrast, tumour infiltration by interleukin (IL)-17A-producing cells, evaluated so far in a limited number of cases (50C200), appears to be associated with unfavourable prognosis.7 8 IL-17A (hereafter referred to as IL-17) is an inflammatory cytokine, secreted by different cell types, including CD4+ T helper cells (Th17),9 10 CTLs, T cells, Tregs,11C13 natural killer (NK) cells, NKT cells, lymphoid tissue inducer (LTi)-like cells and neutrophils.14 15 IL-17 plays a prominent role in protective immune responses against bacterial and fungal infections and in the pathogenesis of inflammatory disorders.9 10 16 Experimental models indicate that IL-17 promotes intestinal tumorigenesis,17C22 either by favouring proliferation of aberrant epithelial cells21 or by inducing IL-6 release by tumour-associated stroma.18 Furthermore, IL-17 promotes angiogenesis through vascular endothelial growth factor (VEGF) production,18 20 thus mediating tumour resistance to antiangiogenic treatments.18 Monoclonal antibodies targeting IL-17/IL-17-receptor, or cytokines, such as IL-23, supporting Th17 development, have been recently developed and their clinical application in several inflammatory and autoimmune diseases is being evaluated.23C25 These reagents may provide a new therapeutic option in CRC.26 However, before testing IL-17/Th17-targeted treatments, a more comprehensive analysis of CRC-infiltrating, IL-17-producing cells is required.27 We evaluated the prognostic significance of IL-17 in a tissue micro-array (TMA) including 1148 CRC cases and we investigated phenotypes and functions of CRC-derived IL-17+ cells. Here we show that CRC-infiltrating IL-17-producing cells, mainly consisting of polyfunctional Th17, do not themselves predict clinical outcome, but rather play a dual role. On the one hand, owing to IL-17 secretion, they favour release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they promote recruitment of beneficial neutrophils and CTLs by secreting specific chemokine and cytokine patterns. Interestingly, the presence of.
