Abstract
Abstract Intratumoral Th17 numbers and local production of IL-17 have been shown to positively correlate with survival of ovarian cancer (OvCa) patients. We demonstrate that the tumor-associated expression of IL-17A in OvCa patients positively correlates with the expression of NOS-2. Our data indicate that the nitric oxide synthase-2 (NOS2/iNOS)- driven NO produced by patients’ myeloid-derived suppressor cells (MDSCs) promotes the development of RORgt(Rorc)+IL-23R+IL-17+ Th17 cells. In addition to the positive impact of the exogenous (MDSC-produced) NO, we show that the development of Th17 cells from naive-, memory-, or tumor-infiltrating CD4+ T cells, driven by IL-1β/IL-6/IL-23/NO-producing MDSCs or by recombinant cytokines (IL-1β/IL-6/IL-23), is associated with the induction of endogenous NOS2 and NO production, and critically depends on NOS2 activity within CD4+ T cells. Inhibition of NOS2 activity or the canonical cGMP/cGK pathway of NO signaling abolishes the de novo induction of Th17 cells and selectively suppresses IL-17 production by established Th17 cells isolated from OvCa patients. The current results provide rationale for targeting NO, NOS2, cGMP, and cGK as new targets to manipulate Th17 responses in cancer.
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