RESUMO
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.
Assuntos
Gangliosídeos/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Apoptose/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/imunologia , Gangliosídeos/metabolismo , Voluntários Saudáveis , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Neoplasias/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/metabolismo , Microambiente Tumoral/imunologiaRESUMO
FOXP3 has been proposed to be critical for the regulatory function of CD4(+)CD25+ T cells and it has been reported that its expression correlates with protection from graft-versus-host-disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Here, by monitoring 28 pediatric HSCT recipients, we found that the levels of FOXP3-mRNA expression in highly enriched CD4(+)CD25+ cells were identical to those in healthy controls irrespective of GvHD status. Moreover, FOXP3-mRNA was abundant in recently in vitro stimulated CD4(+)CD25+ cells that lacked regulatory function. Together these findings suggest that FOXP3-mRNA expression primarily reflects CD4(+)CD25+ cell frequency rather than defining the regulatory potential of CD4(+)CD25+ T cells and GvHD risk after HSCT.