title: Decitabine facilitates immune recognition of sarcoma cells by upregulating CT antigens, MHC molecules, and ICAM-1.
abstract: Rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma are the most common types of sarcoma in children. Despite standard therapy, nearly one third of the patients with Ewing's sarcoma relapse, and there are limited options with curative potential. Immunotherapy is a promising approach as it can target tumor-specific antigens that are specifically expressed on tumors while sparing non-malignant cells. We have demonstrated that a demethylating chemotherapeutic drug, 5-aza-2'-deoxycytidine (decitabine, DAC) can upregulate the expression of cancer-testis (CT) antigens, MHC molecules, and intracellular cell adhesion molecule-1 on pediatric sarcoma cell lines, resulting in enhanced killing of tumor cells by CT antigen-specific cytotoxic T lymphocytes derived from pediatric sarcoma patients. A significant increase in the mRNA expression levels of MAGE-A1 and MAGE-A3 were found in 70 %, and NY-ESO-1 in 80 % of the sarcoma lines following exposure to pharmacological levels of DAC. The high expression levels of MAGE-A1, MAGE-A3, and NY-ESO-1 were sustained in sarcoma lines and primary tumor lines over 30 days after the cessation of DAC. Furthermore, DAC treatment induced upregulation of MAGE-A1, MAGE-A3, or NY-ESO-1 protein expression in seven of nine lines studied. These studies show that demethylating chemotherapy could be combined with CT antigen-directed immunotherapy for treating pediatric sarcoma.
authors.affiliation: Department of Pediatrics, Division of Hematology / Oncology, University of Louisville, Baxter 1, Room 204B, 570 South Preston Street, Louisville, KY, 40202, USA, d.kolaserikrishnadas@louisville.edu.
authors.forename: Deepa Kolaseri
authors.initials: DK
authors.lastname: Krishnadas
authors.forename: Lei
authors.initials: L
authors.lastname: Bao
authors.forename: Fanqi
authors.initials: F
authors.lastname: Bai
authors.forename: Satheesh Cheeyancheri
authors.initials: SC
authors.lastname: Chencheri
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lucas
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077209:Decitabine; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D058950:Melanoma-Specific Antigens / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D012509:Sarcoma / Q000188:drug therapy* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; C104948:CTAG1B protein, human; D006680:HLA Antigens; C072011:MAGEA1 protein, human; C072013:MAGEA3 protein, human; D058950:Melanoma-Specific Antigens; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D018799:Intercellular Adhesion Molecule-1; D000077209:Decitabine; D001374:Azacitidine