title: De novo induction of a cancer/testis antigen by 5-aza-2'-deoxycytidine augments adoptive immunotherapy in a murine tumor model.
abstract: Recent studies suggest that immunotherapy targeting specific tumor-associated antigens (TAAs) may be beneficial in cancer patients. However, most of these TAAs are tumor type specific and heterogeneous among patients, thus limiting their applications. Here, we describe the de novo induction of a cancer/testis antigen (CTA) for immunotherapy of tumors of various histologies. The murine CTA P1A, normally expressed only in a few tumor lines, could be induced de novo in all P1A-negative cancer lines of eight histologic origins in vitro and in various murine xenografts by systemic administration of 5-aza-2'-deoxycytidine. The induction of P1A expression correlated strongly with demethylation of the CpG island in the promoter region of this gene. The induced antigen was processed and presented properly for recognition by H-2L(d)-restricted P1A-specific CTLs. The combination of a demethylating agent and adoptive transfer of P1A-specific CTL effectively treated lung metastases in syngeneic mice challenged with P1A-negative 4T1 mammary carcinoma cells. These data show a novel strategy of combined chemoimmunotherapy of cancer targeting a CTA induced de novo in a broad range of tumor histologies, and support further evaluation of chromatin-remodeling agents for human cancer therapy.
authors.affiliation: Thoracic Oncology Section and Tumor Immunology Section, Surgery Branch, National Cancer Institute/NIH, Bethesda, MD 20892, USA. guozs@upmc.edu
authors.forename: Z Sheng
authors.initials: ZS
authors.lastname: Guo
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hong
authors.forename: Kari R
authors.initials: KR
authors.lastname: Irvine
authors.forename: G Aaron
authors.initials: GA
authors.lastname: Chen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Spiess
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Zeng
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.forename: Dao M
authors.initials: DM
authors.lastname: Nguyen
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000502:physiology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D020869:Gene Expression Profiling; D006801:Humans; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D002843:Chromatin; C507749:cancer-testis antigen P1A, mouse; D000077209:Decitabine; D001374:Azacitidine