Interleukin 2-mediated Conversion of Ovarian Cancer-associated CD4+ Regulatory T Cells Into Proinflammatory Interleukin 17-producing Helper T Cells

Abstract

Epithelial ovarian cancer (EOC) is a highly inflammatory malignancy, characterized by the presence, at the tumor site, of regulatory T cells (Treg) that suppress antitumor immunity. Recently, a new lineage of CD4+ T cells producing the proinflammatory cytokine interleukin (IL)-17 [T helper (TH) 17] has been identified as a major player in some autoimmune diseases. The role of TH17 cells in cancer, however, and their relationship with coexisting Treg populations, whose differentiation is partially controlled by the same mediators (ie, transforming growth factor-beta), are yet unclear. Here, we show that EOC-associated/infiltrating lymphocytes derived by culturing tumor samples in the presence of IL-2 contain significant frequencies of TH17 cells, coproducing interferon-gamma (IFN)-gamma and tumor necrosis factor (TNF)-alpha, which represent, in some cases, up to 40% of total CD4+ T cells. TH17 cells were also detected ex vivo, but at lower proportions than in cultured tumor-infiltrating lymphocytes/tumor-associated lymphocytes, and were confined to the CD4+CD25- fraction. Remarkably, analysis of EOC-associated conventional CD4CD25 T cell and Treg populations isolated ex vivo from tumor samples by cell sorting and cultured with tumor-associated CD3- cells in the presence of IL-2 revealed that EOC Treg stimulated under these conditions were rapidly converted into TH17 cells, down-regulated FOXP3 expression, and lost their suppressive capacity. Thus, although the impact of TH17 cells on the evolution of EOC remains to be established, our data suggest that local IL-2 treatment in ovarian cancer may result in the conversion of tumor-associated Treg into TH17 cells, relieve Treg-mediated suppression, and contribute to enhance antitumor immunity.

Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions

“…Plasticity has been demonstrated in the tumor microenvironment (33), and our data extend this finding to the environment of the allogeneic endothelium under inflammatory conditions such as those observed following organ transplantation.…”

“…HMEC-1 was provided by A. Kesikli (University of Regensburg, Germany) and used between passages eight and 15 (33). Primary ECs (i.e., HDMECs; Lonza) were used between passages three and six (34,35).…”

Characterization of Gliadin-Specific Th17 Cells from the Mucosa of Celiac Disease Patients

“…Th is result adds a new COLON/SMALL BOWEL Human Gliadin-Specific Th17 Cells from Treg cells becoming Th 17 cells, as this population does not retain any of the characteristics of Treg cells, with the exception of its ability to produce TGF β ( 48,49 ). However, our data do not formally exclude this possibility, which needs to be further explored in detail in CD.…”

Tumor infiltrating lymphocytes in ovarian cancer

“…Leveque et al showed that doses of IL-2 converted CD4C regulatory cells into IL-17 secreting helper T-cells that potentially lost their regulatory activity in ovarian cancer tumor specimens. 128 Lymphodepletion prior to TIL based adoptive immunotherapy has greatly improved the success rate in metastatic melanoma treatment [58][59][60] and extends in-vivo survival of transferred TILs. 129 Some authors suggest that profound lymphoablation with stem-cell rescue may further enhance immunotherapies in cancer, and have shown significant results in animal models, although they caution about adopting this method into clinical practice.…”