title: T lymphocyte-derived TNF and IFN-γ repress HFE expression in cancer cells.
abstract: The immune system and tumors are closely intertwined initially upon tumor development. During this period, tumors evolve to promote self-survival through immune escape, including by targeting crucial components involved in the presentation of antigens to the immune system in order to avoid recognition. Accordingly, components involved in MHC I presentation of tumor antigens are often mutated and down-regulated targets in tumors. On the other hand, the immune system has been shown to influence tumors through production of immunosuppressive cytokines, recruitment and polarization of cells favoring or impeding tumor escape or through production of anti-tumor cytokines promoting tumor rejection. We previously discovered that the hemochromatosis protein HFE, a negative regulator of iron absorption, dampens classical MHC I antigen presentation. In this study, we evaluated the impact of activated T lymphocytes purified from peripheral blood mononuclear cells (PBMC) on HFE expression in tumor cell lines. We co-cultured tumor cell lines from melanoma, lung, and kidney cancers with anti-CD3-activated PBMC and established that HFE expression is increased in tumor cell lines compared to healthy tissues, whilst being down-regulated significantly upon exposure to activated PBMC. HFE down-regulation was mediated by both CD4 and CD8 T lymphocytes, through production of soluble mediators, namely TNF and IFN-γ. These results suggest that the immune system may modulate tumor HFE expression in inflammatory conditions in order to regulate MHC I antigen presentation and promote tumor clearance.
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal, Montréal, Québec, Canada H2X 0A9; Département de Médecine, Université de Montréal, Montréal, Québec, Canada H3C 3J7.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reuben
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal, Montréal, Québec, Canada H2X 0A9; Département de Médecine, Université de Montréal, Montréal, Québec, Canada H3C 3J7.
authors.forename: Jessica
authors.initials: J
authors.lastname: Godin-Ethier
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal, Montréal, Québec, Canada H2X 0A9; Département de Médecine, Université de Montréal, Montréal, Québec, Canada H3C 3J7. Electronic address: manuela.santos@umontreal.ca.
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Santos
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal, Montréal, Québec, Canada H2X 0A9; Département de Médecine, Université de Montréal, Montréal, Québec, Canada H3C 3J7. Electronic address: rejean.lapointe1@videotron.ca.
authors.forename: Réjean
authors.initials: R
authors.lastname: Lapointe
mesh_terms: D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015536:Down-Regulation / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D057809:HEK293 Cells; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; C573415:IFNG protein, human; D008565:Membrane Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Co-cultures; HFE; T lymphocytes; Tumor cells