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IFN-? and tumor gangliosides: Implications for the tumor microenvironment.

ABSTRACT: Gangliosides shed by tumors into their microenvironment (TME) are immunoinhibitory. Interferon-? (IFN-?) may boost antitumor immune responses. Thus we wondered whether IFN-? would counteract tumor ganglioside-mediated immune suppression. To test this hypothesis, we exposed human monocyte-derived LPS-activated dendritic cells (DC) to IFN-? 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-? 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-?-signaling axis, was active. The combination, IFN-? and DC ganglioside enrichment, markedly impaired DC stimulatory potential of CD8+ T-cells. We suggest that gangliosides and IFN-? may act in concert as immunosuppressive mediators in the TME, possibly promoting tumor progression.

SUBMITTER: Dillinger B

PROVIDER: S-EPMC5826801 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Dillinger Barbara B Ahmadi-Erber Sarah S Lau Manuel M Hoelzl Markus A MA Erhart Friedrich F Juergens Birgit B Fuchs Dietmar D Heitger Andreas A Ladisch Stephan S Dohnal Alexander M AM

Cellular immunology 20180202

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-induc ...[more]

PMID: 29402391

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Project description:Immune checkpoint inhibitors (ICIs) have had a profound impact on the treatment of many tumors; however, their effectiveness against triple-negative breast cancers (TNBCs) has been limited. One factor limiting responsiveness of TNBCs to ICIs is a lack of functional tumor-infiltrating lymphocytes (TILs) in 'non-inflamed' or 'cold' tumor immune microenvironments (TIMEs), although by unknown mechanisms. Targeting MUC1-C in a mouse transgenic TNBC tumor model increases cytotoxic tumor-infiltrating CD8+ T cells (CTLs), supporting a role for MUC1-C in immune evasion. The basis for these findings and whether they extend to human TNBCs are not known. Human TNBC cells silenced for MUC1-C using short hairpin RNAs (shRNAs) were analyzed for the effects of MUC1-C on global transcriptional profiles. Differential expression and rank order analysis was used for gene set enrichment analysis (GSEA). Gene expression was confirmed by quantitative reverse-transcription PCR and immunoblotting. The The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets were analyzed for effects of MUC1 on GSEA, cell-type enrichment, and tumor immune dysfunction and exclusion. Single-cell scRNA-seq datasets of TNBC samples were analyzed for normalized expression associations between MUC1 and selected genes within tumor cells. Our results demonstrate that MUC1-C is a master regulator of the TNBC transcriptome and that MUC1-C-induced gene expression is driven by STAT1 and IRF1. We found that MUC1-C activates the inflammatory interferon (IFN)-γ-driven JAK1→STAT1→IRF1 pathway and induces the IDO1 and COX2/PTGS2 effectors, which play key roles in immunosuppression. Involvement of MUC1-C in activating the immunosuppressive IFN-γ pathway was extended by analysis of human bulk and scRNA-seq datasets. We further demonstrate that MUC1 associates with the depletion and dysfunction of CD8+ T cells in the TNBC TIME. These findings demonstrate that MUC1-C integrates activation of the immunosuppressive IFN-γ pathway with depletion of TILs in the TNBC TIME and provide support for MUC1-C as a potential target for improving TNBC treatment alone and in combination with ICIs. Of translational significance, MUC1-C is a druggable target with chimeric antigen receptor (CAR) T cells, antibody-drug conjugates (ADCs) and a functional inhibitor that are under clinical development.

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IFN-? and tumor gangliosides: Implications for the tumor microenvironment.

Publications

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

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