Abstract 3546: IL-17 production by tumor-infiltrating Th17 cells favors inflammation and promotes survival in human colorectal cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.3546-3546
• Main Authors: Amicarella, Francesca, Huber, Xaver, Adamina, Michel, Zuber, Markus, Oertli, Daniel, Lugli, Alessandro, Zlobec, Inti, Trapani, Francesca, Eppenberger, Serenella, Terracciano, Luigi Maria, Zajac, Paul, Spagnoli, Giulio Cesare, Iezzi, Giandomenica
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-3546

Background and aims: Evidence from experimental models suggests that IL-17 and T helper (Th)-17 cells may contribute to anti-tumor immune responses. The role played by IL-17 in human cancers remains however, to be clarified. We have investigated phenotypes and prognostic significance of IL-17-producing and IL-17-responsive cells in human colorectal cancer (CRC). Methods: Expression of IL-17 and IL-17 receptors (IL-17R) A and C was investigated on freshly isolated CRC specimens by flow cytometry, in combination with surface molecules identifying specific cell populations. IL-17 and IL-17RA expression was also evaluated by immunohistochemistry on a tissue micro-array (TMA) including 1420 cases of primary CRC with full clinico-pathological data. IL-17R-expressing cell populations were tested for their responsiveness to IL-17 in vitro. In particular, proliferation rates were measured by 3H-thymidine incorporation and production of inflammatory cytokine/chemokines was evaluated at gene and protein level by real-time PCR and ELISA. Results: CRC-infiltrating IL-17-producing cells were exclusively comprised within the lymphocyte population and expressed CD4, but not CD8, and surprisingly, Foxp3 molecules. In contrast, no NK, NKT, gamma-delta T and lymphoid tissue-inducer-like cells were found within the IL-17+ fraction. High infiltration by IL-17 producing cells significantly correlated with low T and N stages, and, most importantly, in the group of mismatch repair (MMR)-proficient CRCs, with prolonged survival time. Interestingly, infiltration by IL-17+ cells was found to be significantly associated to that of CD16+ myeloid cells. On primary CRCs and established cell lines, IL-17RA and C were found to be expressed only on a subpopulation of tumor cells. In contrast, all tumor-associated stromal cells expressed IL-17RC at high levels, and at lower extent, IL-17RA. Conversely, tumor-infiltrating CD16+ myeloid cells exhibited high expression of IL-17RA, but did not express IL-17RC. Prognostic significance of IL-17R expression on primary CRCs is currently being evaluated. In vitro exposure of CRC cells to IL-17 did not significantly enhance tumor cell proliferation, neither promoted the release of inflammatory cytokines, but strongly induced the expression of CXCL1, XCL1 and CXCL16 chemokines. On CD16+ myeloid cells, IL-17 promoted the release of IL-6 and the expression of chemotactic factors, including CXCL1, XCL1, CXCL10, CXCL11, CCL2, CCL3, and CCL20. Finally, IL-