Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/21708
Title: Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade.
Authors: Jacquelot, Nicolas;Yamazaki, Takahiro;Roberti, Maria P;Duong, Connie P M;Andrews, Miles C;Verlingue, Loic;Ferrere, Gladys;Becharef, Sonia;Vétizou, Marie;Daillère, Romain;Messaoudene, Meriem;Enot, David P;Stoll, Gautier;Ugel, Stefano;Marigo, Ilaria;Foong Ngiow, Shin;Marabelle, Aurélien;Prevost-Blondel, Armelle;Gaudreau, Pierre-Olivier;Gopalakrishnan, Vancheswaran;Eggermont, Alexander M;Opolon, Paule;Klein, Christophe;Madonna, Gabriele;Ascierto, Paolo A;Sucker, Antje;Schadendorf, Dirk;Smyth, Mark J;Soria, Jean-Charles;Kroemer, Guido;Bronte, Vincenzo;Wargo, Jennifer;Zitvogel, Laurence
Affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Faculté de Médecine-Université Paris-Sud, Le Kremlin-Bicêtre, France
CIC Biotherapie IGR Curie, CIC1428, Gustave Roussy Cancer Campus, Villejuif, France
Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
Université Pierre et Marie Curie, Paris, France
Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
INSERM, U1016, Institut Cochin, Paris, France
CNRS, UMR8104, Paris, France
Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France
Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
School of Medicine, University of Queensland, Herston, QLD, Australia
INSERM U1015, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France
Université Paris-Saclay, Le Kremlin-Bicêtre, France
Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France
Department of Medicine, Verona University Hospital, Verona, Italy
Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France
INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy
Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany & German Cancer Consortium (DKTZ), Heidelberg, Germany
Department of Medicine, Verona University Hospital, Verona, Italy
Issue Date: 3-Sep-2019
EDate: 2019-09-03
Citation: Cell research 2019; online first: 3 September
Abstract: 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 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNβ transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 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 NOS2 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21708
DOI: 10.1038/s41422-019-0224-x
ORCID: 0000-0001-5788-6840
0000-0002-9067-8557
0000-0003-1231-8641
0000-0002-7268-5905
0000-0002-8322-475X
0000-0003-3524-7858
0000-0001-7098-7240
0000-0002-9334-4405
0000-0003-3438-7576
PubMed URL: 31481761
Type: Journal Article
Appears in Collections:Journal articles

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