IFN-γ and tumor gangliosides: Implications for the tumor microenvironment

Abstract

Gangliosides shed by tumors into their microenvironment (TME) are immunoinhibitory. Interferon-γ (IFN-γ) may boost antitumor immune responses. Thus we wondered whether IFN-γ would counteract tumor ganglioside-mediated immune suppression. To test this hypothesis, we exposed human monocyte-derived LPS-activated dendritic cells (DC) to IFN-γ and to a highly purified ganglioside, GD1a. DC ganglioside exposure decreased TLR-dependent p38 signaling, explaining the previously observed ganglioside-induced down-modulation of pro-inflammatory surface markers and cytokines. Strikingly, while increasing LPS-dependent DC responses, IFN-γ unexpectedly did not counteract the inhibitory effects of GD1a. Rather, induction of indoleamine 2,3-dioxygenase (IDO1), and expression of STAT1/IRF-1 and programmed cell death ligand (PD-L1), indicated that the immunoinhibitory, not an immune stimulatory, IFN-γ-signaling axis, was active. The combination, IFN-γ and DC ganglioside enrichment, markedly impaired DC stimulatory potential of CD8 T-cells. We suggest that gangliosides and IFN-γ may act in concert as immunosuppressive mediators in the TME, possibly promoting tumor progression.

An ultrasound-driven immune-boosting molecular machine for systemic tumor suppression

“…The antitumor functions of these CD8 + T cells were further confirmed by intracellular interferon-γ (IFN-γ) staining and in vivo cytotoxicity assay. IFN-γ has been widely recognized for its proinflammatory capability in mediating antitumor immunity ( 44 ). Consistently, a higher amount of IFN-γ production was found in the tumor tissue sections from C34 + US–treated group ( Fig.…”

Immunomodulatory Effects of Phosphorylated Radix Cyathulae officinalis Polysaccharides in Immunosuppressed Mice

“…[28]. In general, Th1-cytokines enhance division and proliferation of lymphocytes, facilitate maturation of DC, and activate Th1-based immune responses [29]. Th2 cytokines, such as IL-4, -5, -6, and -10, promote Th2-type immune responses and increase antibody production [30,31].…”

Human repair‐related Schwann cells adopt functions of antigen‐presenting cells in vitro

“…If not stated otherwise, the staining procedure was performed on 4 C. For all phenotyping experiments, cells were cultured in duplicates in each condition. Human repair-related SCs were cultured in the presence of IFNγ (10 3 U/mL, Bio-Techne Ltd.), LPS (10 ng/mL, Sigma-Aldrich,), Poly:IC (2 μg/mL, Bio-Techne Ltd.) crosslinked CD40L (500 ng/mL, Bio-Techne Ltd.) and IL-1β (10 4 U/mL Bio-Techne Ltd.) for 24 h. Concentrations of cytokines and ligands were chosen according to the manufacturer's recommendations and are in line with previously published levels released by antigen-presenting cells or lymphocytes in vitro or in peripheral blood plasma (Dillinger et al, 2018). Cells were harvested with Accutase (Sigma-Aldrich) and transferred into FACS tubes containing 200 μl FACS buffer (0.1% BSA and 0.05% natrium acides in 1x PBS).…”