Restoration of immune response gene induction in trophoblast tumor cells associated with cellular senescence.
Trophoblast cells and many cancer cells that harbor foreign antigens may evade immunity by epigenetic silencing of key immune response genes, including MHC class I and II and CD40. Chromatin active agents, such as histone deacetylase inhibitors (HDACi), induce immune response gene expression but often the expression levels are low and the cells lack a robust antigen presentation response. We show here that pre-treatment of trophoblast cells and certain cancer cells with agents that activate stress pathways (Ras oncogene, PMA or H2O2) and induce senescence can substantially enhance the induction of immune response genes (MHC class II, CD40, MICA, MICB) by HDACi and restore a vigorous IFN-gamma response in trophoblast cells and tumor cells. These results could potentially impact the development of novel anti-cancer therapeutic strategies.
Gregorie
Christopher J
CJ
Roswell Park Cancer Institute, Laboratory of Molecular Medicine, Department of Immunology, Elm & Carlton Streets, Buffalo, NY 14263, USA.
Wiesen
Jennifer L
JL
Magner
William J
WJ
Lin
Athena W
AW
Tomasi
Thomas B
TB
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016922:Cellular Senescence / Q000276:immunology*; D002822:Choriocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000276:immunology; D005260:Female; D020868:Gene Silencing / Q000187:drug effects / Q000276:immunology; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018384:Oxidative Stress / Q000276:immunology; D011247:Pregnancy; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D014327:Trophoblasts / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology
D019013:CD40 Antigens; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D007371:Interferon-gamma