Abstract 3546: IL-17 production by tumor-infiltrating Th17 cells favors inflammation and promotes survival in human colorectal cancer
Authors: Francesca Amicarella, Xaver Huber, Michel Adamina, Markus Zuber, Daniel Oertli, Alessandro Lugli, Inti Zlobec, Francesca Trapani, Serenella Eppenberger, Luigi Maria Terracciano, Paul Zajac, Giulio Cesare Spagnoli, Giandomenica Iezzi
Journal: Cancer Research (2012)

Abstract 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-17 markedly enhanced IL-6 production by stromal cells. Conclusions: Tumor-infiltrating Th17 cells appear to play a beneficial role in human CRC, possibly by inducing the expression of inflammatory and chemotactic factors by tumor-associated stromal and myeloid cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3546. doi:1538-7445.AM2012-3546