title: Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.
abstract: Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Wang
authors.forename: Zhen-Yang
authors.initials: ZY
authors.lastname: Mei
authors.forename: Ji-Hao
authors.initials: JH
authors.lastname: Zhou
authors.forename: Yu-Shi
authors.initials: YS
authors.lastname: Yao
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Li
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Xu
authors.forename: Jing-Xin
authors.initials: JX
authors.lastname: Li
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Gao
authors.forename: Min-Hang
authors.initials: MH
authors.lastname: Zhou
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Jiang
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Xue-Chun
authors.initials: XC
authors.lastname: Lu
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Shi
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Luo
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Wang
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Qu
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Bai
authors.forename: Li
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D020014:K562 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D020298:U937 Cells
chemical_list: D000964:Antimetabolites, Antineoplastic; D018122:B7-1 Antigen; D007376:Interleukin-2; D000077209:Decitabine; D007371:Interferon-gamma; D001374:Azacitidine