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Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade

查看全文 作　　者：Nicolas [1,2,3,4,26]Jacquelot;Takahiro [1,3]Yamazaki;Maria [1,3,5]PRoberti;Connie [1,3]PMDuong;Miles [6,7,8]CAndrews;Loic [3,9]Verlingue;Gladys [1,3,5]Ferrere;Sonia [1,3]Becharef;Marie [1,3]Vetizou;Romain [1,3]Daillere;Meriem [1,3]Messaoudene;David [3,10]PEnot;Gautier [10,11,12,13,14]Stoll;Stefano [15]Ugel;Maria [16]Marigo;Shin Foong [17,18]Ngiow;Aurelien [1,2,3]Marabelle;Armelle Prevost-[14,19,20]Blondel;Pierre-Olivier [6]Gaudreau;Vancheswaran [6]Gopalakrishnan;Alexander [3]MEggermont;Paule [3]Opolon;Christophe [11]Klein;Gabriele [21]Madonna;Paolo [21]AAscierto;Antje [22]Sucker;Dirk [22]Schadendorf;Mark JSm [17,18]yth;Jean-Charles [2,3,4,9]Soria;Guido [2,3,4,10,11,12,13,14,23,24]Kroemer;Vincenzo [15]Bronte;Jennifer [6,25]Wargo;and Laurence [1,2,3,4,5]Zitvogel 高影响力作者 机构地区：[1]INSERM U1015,Gustave Roussy,114 rue Edouard Vaillant,94805 Villejuif Cedex,France;[2]Universite Paris-Saclay,Le Kremlin-Bic§tre,France;[3]lnstitut de Cancerologie Gustave Roussy Cancer Campus(GRCC),114 rue Edouard Vaillant,Villejuif,France;[4]Faculte de Medecine-Universite Paris-Sud,Le Kremlin-Bicetre,France;[5]CIC Biotherapie IGR Curie,CIC1428,Gustave Roussy Cancer Campus,Villejuif,France;[6]Department of Surgical Oncology,MD Anderson Cancer Center,Houston,TX,USA;[7]Ojivia Newton-John Cancer Research Institute,Heidelberg,VIC,Australia;[8]School of Cancer Medicine,La Trobe University,Heidelberg,VIC,Australia;[9]Drug Development Department(DITEP),Gustave Roussy,Universite Paris-Sud,Universite Paris-Saclay,Villejuif,France;[10]Metabolomics and Cell Biology Platforms,Gustave Roussy Cancer Campus,Villejuif,France;[11]INSERM U1138,Centre de Recherche des Cordeliers,Paris,France;[12]Equipe 11 labellisee par la Ligue contre le Cancer,Centre de Recherche des Cordeliers,Paris,France;[13]Universite Pierre et Marie Curie,Paris,France;[14]Universite Paris Descartes,Sorbonne Paris Cite,Paris,France;[15]Department of Medicine,Verona University Hospital,Verona,Italy;[16]lstituto Oncologico Veneto IOV-IRCCS,Padova,Italy;[17]lmmunology in Cancer and Infection Laboratory,QIMR Berghofer Medical Research Institute,Herston,QLD,Australia;[18]School of Medicine,University of Queensland,Herston,QLD,Australia;[19]INSERM,U1016,Institut Cochin,Paris,France;[20]CNRS,UMR8104 Paris,France;[21]Melanoma Cancer Immunotherapy and Innovative Therapy Unit,Istituto Nazionale Tumori IRCCS Fondazione,'G.Pascale',Napoli,Italy;[22]Department of Dermatology,University Hospital,University Duisburg-Essen,Essen,Germany&German Cancer Consortium(DKTZ),Heidelberg,Germany;[23]Pole de Biologie,Hopital Europeen Georges Pompidou,AP-HP,Paris,France;[24]Department of Women's and Children^Health,Karolinska Institute,Karolinska University Hospital,Stockholm,Sweden;[25]Department of Genomic Medicine,The University of Texas MD Anderson Cancer Center,Houston,TX,USA;[26]Present address:Immunology Division,The Walter and Eliza Hall Institute of Medical Research,Melbourne,VIC,Australia高影响力机构 出　　处：《Cell Research》索引2019年第29卷第10期,共16页高影响力期刊 摘　　要：PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy.Delineating mechanisms of secondary resistance to this strategy is increasingly important.Here,we identified the deleterious role of signaling via the type I interferon(IFN)receptor in tumor and antigen presenting cells,that induced the expression of nitric oxide synthase 2(N0S2),associated with intratumor accumulation of regulatory T cells(Treg)and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody(mAb).Sustained IFNP transcription was observed in resistant tumors,in turn inducing PD-L1 and N0S2 expression in both tumor and dendritic cells(DC).Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb,pharmacological or genetic inhibition of N0S2 maintained long-term control of tumors by PD-1 blockade,through reduction of Treg and DC activation.Resistance to immunotherapies,including anti-PD-1 mAb in melanoma patients,was also correlated with the induction of a type I IFN signature.Hence,the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy. 关 键 词：INTERFERON SUSTAINED RESISTANCE
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