cGAS-STING信号通路与肿瘤相关性研究进展
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摘要
cGAS-STING信号通路是细胞内一条重要的免疫应答通路,通过调节起始免疫和适应性免疫在病原体感染和肿瘤中发挥重要调控作用,并与多种人类自免疫疾病相关。全文就cGAS-STING信号通路的调控、与肿瘤相关性和免疫治疗等方面进行阐述,旨在为靶向该通路的免疫治疗提供理论基础。
cGAS-STING signaling pathway is one of the most significant immune response pathway in cells. Through the regulation of innate immunity and adaptive immunity,it plays an important role in pathogen infection,tumors,as well as several human autoimmune diseases. This article reviews the function,regulation of the cGAS-STING signal pathway,its correlation with tumor and application in immunity therapy,which may provide the information for anticancer therapy.
cGAS-STING signaling pathway is one of the most significant immune response pathway in cells. Through the regulation of innate immunity and adaptive immunity,it plays an important role in pathogen infection,tumors,as well as several human autoimmune diseases. This article reviews the function,regulation of the cGAS-STING signal pathway,its correlation with tumor and application in immunity therapy,which may provide the information for anticancer therapy.
引文
[1]Bose D.CGAS/STING pathway in cancer:jekyll and hyde story of cancer immune response[J].Int J Mol Sci,2017,18(11):piiE2456.
[2]Lio CW,McDonald B,Takahashi M,et al.CGAS-STINGsignaling regulates initial innate control of cytomegalovirus infection[J].J Virol,2016,90(17):7789-7797.
[3]Liu S,Zhao K,Su X,et al.Mita/Sting and its alternative splicing isoform mrp restrict hepatitis B virus replication[J].PLoS One,2017,12(1):e0169701.
[4]Ding S,Diep J,Feng N,et al.Stag2 deficiency induces interferon responses via Cgas-Sting pathway and restricts virus infection[J].Nat Commun,2018,9(1):1485.
[5]Anghelina D,Lam E,Falck-Pedersen E.Diminished innate antiviral response to adenovirus vectors in Cgas/Sting-Deficient mice minimally impacts adaptive immunity[J].J Virol,2016,90(13):5915-5927.
[6]Iurescia S,Fioretti D,Rinaldi M.Targeting cytosolic nucleic acid-sensing pathways for cancer immunotherapies[J].Front Immunol,2018,9:711.
[7]Harding SM,Benci JL,Irianto J,et al.Mitotic progression following DNA damage enables pattern recognition within micronuclei[J].Nature,2017,548(7668):466-470.
[8]Li T,Chen ZJ.The Cgas-Cgamp-Sting pathway connects DNA damage to inflammation,senescence,and cancer[J].J Exp Med,2018,215(5):1287-1299.
[9]Xu MM,Pu Y,Han D,et al.Dendritic cells but not macrophages sense tumor mitochondrial DNA for crosspriming through signal regulatory protein alpha signaling[J].Immunity,2017,47(2):363-373,e365.
[10]Konno H,Konno K,Barber GN.Cyclic dinucleotides trigger Ulk1(Atg1)phosphorylation of sting to prevent sustained innate immune signaling[J].Cell,2013,155(3):688-698.
[11]Gray EE,Treuting PM,Woodward JJ,et al.Cutting edge:cgas is required for lethal autoimmune disease in the trex1-deficient mouse model of aicardi-goutieres syndrome[J].J Immunol,2015,195(5):1939-1943.
[12]Hartlova A,Erttmann SF,Raffi FA,et al.DNA damage primes the typeⅠinterferon system via the cytosolic DNA sensor sting to promote anti-microbial innate immunity[J].Immunity,2015,42(2):332-343.
[13]Ansari MA,Dutta S,Veettil MV,et al.Herpesvirus genome recognition induced acetylation of nuclear IFI16is essential for its cytoplasmic translocation,inflammasome and IFN-beta responses[J].PLoS Pathogens,2015,11(7):40.
[14]Mankan AK,Schmidt T,Chauhan D,et al.Cytosolic RNA:DNA hybrids activate the cgas-sting Axis[J].EMBOJ,2014,33(24):2937-2946.
[15]Gehrke N,Mertens C,Zillinger T,et al.Oxidative damage of DNA confers resistance to cytosolic nuclease trex1degradation and potentiates sting-dependent immune sensing[J].Immunity,2013,39(3):482-495.
[16]Liang Q,Seo GJ,Choi YJ,et al.Crosstalk between the Cgas DNA sensor and beclin-1 autophagy protein shapes innate antimicrobial immune responses[J].Cell Host Microbe,2014,15(2):228-238.
[17]Wang PH,Fung SY,Gao WW,et al.A novel transcript isoform of sting that sequesters cgamp and dominantly inhibits innate nucleic acid sensing[J].Nucleic Acids Res,2018,46(8):4054-4071.
[18]Li XD,Wu JX,Gao DX,et al.Chen.Pivotal roles of cgascgamp signaling in antiviral defense and immune adjuvant effects[J].Science,2013,341(6152):1390-1394.
[19]Li T,Cheng H,Yuan H,et al.Antitumor activity of cgamp via stimulation of cgas-cgamp-sting-irf3 mediated innate immune response[J].Sci Rep,2016,6:19049.
[20]Durante M,Formenti SC.Radiation-induced chromosomal aberrations and immunotherapy:micronuclei,cytosolic dna,and interferon-production pathway[J].Front Oncol,2018,8:192.
[21]Deng L,Liang H,Xu M,et al.Sting-dependent cytosolic dna sensing promotes radiation-induced typeⅠinterferondependent antitumor immunity in immunogenic tumors[J].Immunity,2014,41(5):843-852.
[22]Weber R,Fleming V,Hu X,et al.Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors[J].Front Immunol,2018,9:1310.
[23]Ahn J,Xia T,Konno H,et al.Inflammation-driven carcinogenesis is mediated through sting[J].Nat Commun,2014,5:5166.
[24]Lemos H,Mohamed E,Huang L,et al.Sting promotes the growth of tumors characterized by low antigenicity via ido activation[J].Cancer Res,2016,76(8):2076-2081.
[25]Chen Q,Boire A,Jin X,et al.Carcinoma-astrocyte gap junctions promote brain metastasis by cgamp transfer[J].Nature,2016,533(7604):493-498.
[26]Wang H,Hu S,Chen X,et al.Cgas is essential for the antitumor effect of immune checkpoint blockade[J].Proc Natl Acad Sci USA,2017,114(7):1637-1642.
[27]Foote JB,Kok M,Leatherman JM,et al.A sting agonist given with ox40 receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice[J].Cancer Immunol Res,2017,5(6):468-479.
[28]Zhang H,Tang K,Zhang Y,et al.Cell-free tumor microparticle vaccines stimulate dendritic cells via cgas/sting signaling[J].Cancer Immunol Res,2015,3(2):196-205.
[29]Bakhoum Samuel F,Bryan Ngo,Ashley M,et al.Chromosomal instability drives metastasis through a cytosolic DNA response[J].Nature,2018,553(7689):467-472.
[30]Xia T,Konno H,Ahn J,et al.Deregulation of Sting signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis[J].Cell Rep,2016,14(2):282-297.
[31]Konno H,Yamauchi S,Berglund A,et al.Suppression of Sting signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production[J].Oncogene,2018,37(15):2037-2051.
[2]Lio CW,McDonald B,Takahashi M,et al.CGAS-STINGsignaling regulates initial innate control of cytomegalovirus infection[J].J Virol,2016,90(17):7789-7797.
[3]Liu S,Zhao K,Su X,et al.Mita/Sting and its alternative splicing isoform mrp restrict hepatitis B virus replication[J].PLoS One,2017,12(1):e0169701.
[4]Ding S,Diep J,Feng N,et al.Stag2 deficiency induces interferon responses via Cgas-Sting pathway and restricts virus infection[J].Nat Commun,2018,9(1):1485.
[5]Anghelina D,Lam E,Falck-Pedersen E.Diminished innate antiviral response to adenovirus vectors in Cgas/Sting-Deficient mice minimally impacts adaptive immunity[J].J Virol,2016,90(13):5915-5927.
[6]Iurescia S,Fioretti D,Rinaldi M.Targeting cytosolic nucleic acid-sensing pathways for cancer immunotherapies[J].Front Immunol,2018,9:711.
[7]Harding SM,Benci JL,Irianto J,et al.Mitotic progression following DNA damage enables pattern recognition within micronuclei[J].Nature,2017,548(7668):466-470.
[8]Li T,Chen ZJ.The Cgas-Cgamp-Sting pathway connects DNA damage to inflammation,senescence,and cancer[J].J Exp Med,2018,215(5):1287-1299.
[9]Xu MM,Pu Y,Han D,et al.Dendritic cells but not macrophages sense tumor mitochondrial DNA for crosspriming through signal regulatory protein alpha signaling[J].Immunity,2017,47(2):363-373,e365.
[10]Konno H,Konno K,Barber GN.Cyclic dinucleotides trigger Ulk1(Atg1)phosphorylation of sting to prevent sustained innate immune signaling[J].Cell,2013,155(3):688-698.
[11]Gray EE,Treuting PM,Woodward JJ,et al.Cutting edge:cgas is required for lethal autoimmune disease in the trex1-deficient mouse model of aicardi-goutieres syndrome[J].J Immunol,2015,195(5):1939-1943.
[12]Hartlova A,Erttmann SF,Raffi FA,et al.DNA damage primes the typeⅠinterferon system via the cytosolic DNA sensor sting to promote anti-microbial innate immunity[J].Immunity,2015,42(2):332-343.
[13]Ansari MA,Dutta S,Veettil MV,et al.Herpesvirus genome recognition induced acetylation of nuclear IFI16is essential for its cytoplasmic translocation,inflammasome and IFN-beta responses[J].PLoS Pathogens,2015,11(7):40.
[14]Mankan AK,Schmidt T,Chauhan D,et al.Cytosolic RNA:DNA hybrids activate the cgas-sting Axis[J].EMBOJ,2014,33(24):2937-2946.
[15]Gehrke N,Mertens C,Zillinger T,et al.Oxidative damage of DNA confers resistance to cytosolic nuclease trex1degradation and potentiates sting-dependent immune sensing[J].Immunity,2013,39(3):482-495.
[16]Liang Q,Seo GJ,Choi YJ,et al.Crosstalk between the Cgas DNA sensor and beclin-1 autophagy protein shapes innate antimicrobial immune responses[J].Cell Host Microbe,2014,15(2):228-238.
[17]Wang PH,Fung SY,Gao WW,et al.A novel transcript isoform of sting that sequesters cgamp and dominantly inhibits innate nucleic acid sensing[J].Nucleic Acids Res,2018,46(8):4054-4071.
[18]Li XD,Wu JX,Gao DX,et al.Chen.Pivotal roles of cgascgamp signaling in antiviral defense and immune adjuvant effects[J].Science,2013,341(6152):1390-1394.
[19]Li T,Cheng H,Yuan H,et al.Antitumor activity of cgamp via stimulation of cgas-cgamp-sting-irf3 mediated innate immune response[J].Sci Rep,2016,6:19049.
[20]Durante M,Formenti SC.Radiation-induced chromosomal aberrations and immunotherapy:micronuclei,cytosolic dna,and interferon-production pathway[J].Front Oncol,2018,8:192.
[21]Deng L,Liang H,Xu M,et al.Sting-dependent cytosolic dna sensing promotes radiation-induced typeⅠinterferondependent antitumor immunity in immunogenic tumors[J].Immunity,2014,41(5):843-852.
[22]Weber R,Fleming V,Hu X,et al.Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors[J].Front Immunol,2018,9:1310.
[23]Ahn J,Xia T,Konno H,et al.Inflammation-driven carcinogenesis is mediated through sting[J].Nat Commun,2014,5:5166.
[24]Lemos H,Mohamed E,Huang L,et al.Sting promotes the growth of tumors characterized by low antigenicity via ido activation[J].Cancer Res,2016,76(8):2076-2081.
[25]Chen Q,Boire A,Jin X,et al.Carcinoma-astrocyte gap junctions promote brain metastasis by cgamp transfer[J].Nature,2016,533(7604):493-498.
[26]Wang H,Hu S,Chen X,et al.Cgas is essential for the antitumor effect of immune checkpoint blockade[J].Proc Natl Acad Sci USA,2017,114(7):1637-1642.
[27]Foote JB,Kok M,Leatherman JM,et al.A sting agonist given with ox40 receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice[J].Cancer Immunol Res,2017,5(6):468-479.
[28]Zhang H,Tang K,Zhang Y,et al.Cell-free tumor microparticle vaccines stimulate dendritic cells via cgas/sting signaling[J].Cancer Immunol Res,2015,3(2):196-205.
[29]Bakhoum Samuel F,Bryan Ngo,Ashley M,et al.Chromosomal instability drives metastasis through a cytosolic DNA response[J].Nature,2018,553(7689):467-472.
[30]Xia T,Konno H,Ahn J,et al.Deregulation of Sting signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis[J].Cell Rep,2016,14(2):282-297.
[31]Konno H,Yamauchi S,Berglund A,et al.Suppression of Sting signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production[J].Oncogene,2018,37(15):2037-2051.