Tumor Microenvironments Direct the Recruitment and Expansion of Human Th17 Cells

Abstract

Although Th17 cells play critical roles in the pathogenesis of many inflammatory and autoimmune diseases, their prevalence among tumor-infiltrating lymphocytes (TILs) and function in human tumor immunity remains largely unknown. We have recently demonstrated high percentages of Th17 cells in TILs from ovarian cancer patients, but the mechanisms of accumulation of these Th17 cells in the tumor microenvironment are still unclear. In this study, we further showed elevated Th17 cell populations in the TILs obtained from melanoma and breast and colon cancers, suggesting that development of tumor-infiltrating CD4+ Th17 cells may be a general feature in cancer patients. We then demonstrated that tumor microenvironmental RANTES and MCP-1 secreted by tumor cells and tumor-derived fibroblasts mediate the recruitment of Th17 cells. In addition to their recruitment, we found that tumor cells and tumor-derived fibroblasts produce a proinflammatory cytokine milieu as well as provide cell–cell contact engagement that facilitates the generation and expansion of Th17 cells. We also showed that inflammatory TLR and nucleotide oligomerization binding domain 2 signaling promote the attraction and generation of Th17 cells induced by tumor cells and tumor-derived fibroblasts. These results identify Th17 cells as an important component of human TILs, demonstrate mechanisms involved in the recruitment and regulation of Th17 cells in tumor microenvironments, and provide new insights relevant for the development of novel cancer immunotherapeutic approaches.

High IL-17 expression is associated with an unfavorable prognosis in thyroid cancer

“…In the present study, the expression of IL-17 protein was decreased in the biopsies of benign lesions (FTA and goiter tissues) when compared to malignant lesions (DTC and MTC). We hypothesize that the increased cytokine expression in the tumor environment may be associated with tumor progression, which is in agreement with the findings of Su et al (34) who demonstrated that a high number of CD4+ Th17 cells were present in melanoma, ovarian, breast and colon carcinomas (34). In the present study, the lymphocytes present in the tumor microenvironment of the MTC group tumors expressed the highest level of IL-17 expression compared with the DTC, FTA and goiter groups.…”

“…The exact mechanism underlying this interaction remains unclear; however; we hypothesize that these molecules are important in the progression of cancer. Th17 cells have been identified in a number of human tumor types, including lymphoma (40), myeloma (41), breast (34) and ovarian cancer (42). In colorectal carcinomas, prognosis is influenced by Th17 expression; patients with high Th17 expression exhibit a poor prognosis (43).…”

Neoplastic Plasma Cells Generate an Inflammatory Environment Within Bone Marrow and Markedly Alter the Distribution of T Cells Between Lymphoid Compartments

“…However, this population still represented less than 1% of the total CD4+ T cell population. The relative frequency of T H 17 cells in blood was not altered and a comparable recruitment of these cells to solid tumours has also been reported [23]. T H 17 cells may play a particularly important role in the development of clinical complications of paraproteinaemia and have been linked to problems such as bone disease.…”

“…The role of regulatory T cells in the development of MM is also under debate and remains controversial [8][9][10][11][12]. T H 17 cells are also of considerable interest in relation to tumour immunity and are increased in both the marrow and blood of patient with paraproteinaemia [13][14][15][16][17][18][19][20][21][22][23].…”

Immunological Processes in Cancer: A Link Between Inflammation and Immunity

“…The cytokines produced by the Treg profile has been described as potent inhibitors of antitumor immune response and are associated with poor prognosis for many types of cancer (Hiraoka et al, 2006;Downey et al, 2007;Fecci et al, 2007;Fu et al, 2007). The discovery of Th17 cells and their role in protecting the host against infectious agents and pathogenesis of several inflammatory and autoimmune diseases resulted in the raise of immunological research and its role in human cancer is still under investigation (Park et al, 2005;Yang and Ansell, 2009;Su et al, 2010).…”