Tumor-Secreted Lactic Acid Promotes IL-23/IL-17 Proinflammatory Pathway

Abstract

IL-23 is a proinflammatory cytokine consisting of a p19 subunit and a p40 subunit that is shared with IL-12. IL-23 is overexpressed in and around tumor tissues, where it induces local inflammation and promotes tumor development. Many tumor cells produce large amounts of lactic acid by altering their glucose metabolism. In this study, we show that lactic acid secreted by tumor cells enhances the transcription of IL-23p19 and IL-23 production in monocytes/macrophages and in tumor-infiltrating immune cells that are stimulated with TLR2 and 4 ligands. DNA elements responsible for this enhancing activity of lactic acid were detected in a 2.7-kb 5′-flanking region of the human IL-23p19 gene. The effect of lactic acid was strictly regulated by extracellular pH. Furthermore, by inducing IL-23 overproduction, lactic acid facilitated the Ag-dependent secretion of proinflammatory cytokine IL-17 but not IFN-γ by TLR ligand-stimulated mouse splenocytes. Interestingly, this effect was observed even in the absence of TLR ligand stimulation. These results suggest that rather than just being a terminal metabolite, lactic acid is a proinflammatory mediator that is secreted by tumor cells to activate the IL-23/IL-17 proinflammatory pathway but not the Th1 pathway. Targeting the lactic acid-induced proinflammatory response may be a useful approach for treating cancer.

Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells

“…In terms of lactate's impact on immune cells, recent studies have shown that lactate suppresses the function of tumor-specific T cells, inhibits tumor specific cytotoxic T cell activity (27), and induces defect in signal transduction (28). Lactate/low pH also alters the Ag-presenting ability of dendritic cells (29), inhibits cytotoxic activity (30), and promotes IL-23/IL-17 proinflammatory pathway (31). These studies have suggested a role for lactate/extracellular pH on tumor growth through inhibition of immune surveillance.…”

Protumor vs Antitumor Functions of IL-17

“…32-52). Many factors released by the tumor cells and the tumor stroma or molecules secreted by tumor-infiltrating immune cells such as TGF-␤, IL-6, PGE 2 , IL-21, IL-23, osteopontin, IL-1␤, and TNF-␣ can play major roles in the induction of Th17 differentiation (53)(54)(55)(56) (Fig. 2).…”

A laktátdehidrogenáz (LDH) prognosztikai jelentősége az onkológiában

“…Kimutatták azt is, hogy például a glioblastomasejtek enzimatikusan aktív LDHA-t szekretálnak, amely a myeloid sejteken az NK Group 2D (NKG2D) ligand expresszióját indukálja, és ennek közvetítésével az NK-sejtek aktivitását csökkenti [66]. A daganatot infiltráló immunsejtekben a tejsav aktiválja az IL-23/IL-17 útvonalat a TLR-stimuláció hatására, amely elősegíti a helyi gyulladásos választ a T-helper (Th) 17/Th23 sejtek által, amely a daganatok kialakulásának és növekedésének kedvez [73]. Ismert az a tény is, hogy a savas környezet, mint fájdalominger, a daganatos fájdalom kialakulásában kulcsszerepet játszik [74].…”