气候变化领域集成服务门户(CCPortal): Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma

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DOI	10.1073/pnas.2013598118
	Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma
	Falahat R.; Berglund A.; Putney R.M.; Perez-Villarroel P.; Aoyama S.; Pilon-Thomas S.; Barber G.N.; Mulé J.J.
发表日期	2021
ISSN	00278424
卷号	118 期号:15
英文摘要	Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell-based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell-based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of cGAS and STING genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and killing by cytotoxic T cells. These findings not only elucidate the contribution of epigenetic processes and specifically DNA methylation in melanoma-intrinsic STING signaling impairment but also highlight their functional significance in mediating tumor-immune evasion and resistance to T cell-based immunotherapies. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antigenicity; DNA methylation; Epigenetic silencing; Immune evasion; STING signaling
语种	英语
scopus关键词	beta interferon; decitabine; DNA; DNA (cytosine 5) methyltransferase 1; DNA methyltransferase 3A; DNA methyltransferase 3B; gamma interferon inducible protein 10; HLA antigen; interferon regulatory factor 3; small interfering RNA; antigenicity; Article; cancer cell; cell killing; controlled study; cytotoxic T lymphocyte; demethylation; DNA methylation; epigenetics; gene; gene function; gene silencing; genetic regulation; HLA matching; human; human cell; immune evasion; inhibition kinetics; melanoma; melanoma cell line; molecular recognition; nuclear reprogramming; priority journal; promoter region; protein expression; protein phosphorylation; signal transduction; stimulator of interferon gene; T lymphocyte; tumor associated leukocyte; upregulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179929
作者单位	Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, United States; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL 33612, United States; Cutaneous Oncology Program, Moffitt Cancer Center, Tampa, FL 33612, United States; Department of Cell Biology, University of Miami, Miller School of Medicine, Miami, FL 33136, United States; Radiation Oncology Program, Moffitt Cancer Center, Tampa, FL 33612, United States
推荐引用方式 GB/T 7714	Falahat R.,Berglund A.,Putney R.M.,et al. Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma[J],2021,118(15).
APA	Falahat R..,Berglund A..,Putney R.M..,Perez-Villarroel P..,Aoyama S..,...&Mulé J.J..(2021).Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma.Proceedings of the National Academy of Sciences of the United States of America,118(15).
MLA	Falahat R.,et al."Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma".Proceedings of the National Academy of Sciences of the United States of America 118.15(2021).