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

      research-article
      1 , 2 , 3 , 4 , 26 , 1 , 3 , 1 , 3 , 5 , 1 , 3 , 6 , 7 , 8 , 3 , 9 , 1 , 3 , 5 , 1 , 3 , 1 , 3 , 1 , 3 , 1 , 3 , 3 , 10 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 1 , 2 , 3 , 14 , 19 , 20 , 6 , 6 , 3 , 3 , 11 , 21 , 21 , 22 , 22 , 17 , 18 , 2 , 3 , 4 , 9 , 2 , 3 , 4 , 10 , 11 , 12 , 13 , 14 , 23 , 24 , , 15 , 6 , 25 , 1 , 2 , 3 , 4 , 5 ,
      Cell Research
      Nature Publishing Group UK
      Tumour immunology, Cancer microenvironment

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          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.

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          Most cited references30

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Is Open Access

            Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

            Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
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              Cancer despite immunosurveillance: immunoselection and immunosubversion.

              Numerous innate and adaptive immune effector cells and molecules participate in the recognition and destruction of cancer cells, a process that is known as cancer immunosurveillance. But cancer cells avoid such immunosurveillance through the outgrowth of poorly immunogenic tumour-cell variants (immunoselection) and through subversion of the immune system (immunosubversion). At the early stages of carcinogenesis, cell-intrinsic barriers to tumour development seem to be associated with stimulation of an active antitumour immune response, whereas overt tumour development seems to correlate with changes in the immunogenic properties of tumour cells. The permanent success of treatments for cancer might depend on using immunogenic chemotherapy to re-establish antitumour immune responses.
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                Author and article information

                Contributors
                kroemer@orange.fr
                Laurence.ZITVOGEL@gustaveroussy.fr
                Journal
                Cell Res
                Cell Res
                Cell Research
                Nature Publishing Group UK (London )
                1001-0602
                1748-7838
                3 September 2019
                3 September 2019
                October 2019
                : 29
                : 10
                : 846-861
                Affiliations
                [1 ]ISNI 0000 0001 2284 9388, GRID grid.14925.3b, INSERM U1015, , Gustave Roussy, ; 114 rue Edouard Vaillant, 94805 Villejuif Cedex, France
                [2 ]ISNI 0000 0004 4910 6535, GRID grid.460789.4, Université Paris-Saclay, ; Le Kremlin-Bicêtre, France
                [3 ]ISNI 0000 0001 2284 9388, GRID grid.14925.3b, Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), ; 114 rue Edouard Vaillant, Villejuif, France
                [4 ]ISNI 0000 0001 2171 2558, GRID grid.5842.b, Faculté de Médecine–Université Paris-Sud, ; Le Kremlin-Bicêtre, France
                [5 ]CIC Biotherapie IGR Curie, CIC1428, Gustave Roussy Cancer Campus, Villejuif, France
                [6 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Surgical Oncology, , MD Anderson Cancer Center, ; Houston, TX USA
                [7 ]GRID grid.482637.c, Olivia Newton-John Cancer Research Institute, ; Heidelberg, VIC Australia
                [8 ]ISNI 0000 0001 2342 0938, GRID grid.1018.8, School of Cancer Medicine, , La Trobe University, ; Heidelberg, VIC Australia
                [9 ]ISNI 0000 0004 4910 6535, GRID grid.460789.4, Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, , Université Paris-Saclay, ; Villejuif, France
                [10 ]Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
                [11 ]GRID grid.417925.c, INSERM U1138, , Centre de Recherche des Cordeliers, ; Paris, France
                [12 ]GRID grid.417925.c, Equipe 11 labellisée par la Ligue contre le Cancer, , Centre de Recherche des Cordeliers, ; Paris, France
                [13 ]ISNI 0000 0001 2308 1657, GRID grid.462844.8, Université Pierre et Marie Curie, ; Paris, France
                [14 ]ISNI 0000 0004 1788 6194, GRID grid.469994.f, Université Paris Descartes, , Sorbonne Paris Cité, ; Paris, France
                [15 ]ISNI 0000 0004 1756 948X, GRID grid.411475.2, Department of Medicine, , Verona University Hospital, ; Verona, Italy
                [16 ]ISNI 0000 0004 1808 1697, GRID grid.419546.b, Istituto Oncologico Veneto IOV-IRCCS, ; Padova, Italy
                [17 ]ISNI 0000 0001 2294 1395, GRID grid.1049.c, Immunology in Cancer and Infection Laboratory, , QIMR Berghofer Medical Research Institute, ; Herston, QLD Australia
                [18 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, School of Medicine, , University of Queensland, ; Herston, QLD Australia
                [19 ]ISNI 0000 0004 0643 431X, GRID grid.462098.1, INSERM, U1016, , Institut Cochin, ; Paris, France
                [20 ]ISNI 0000 0001 2112 9282, GRID grid.4444.0, CNRS, ; UMR8104 Paris, France
                [21 ]ISNI 0000 0001 0807 2568, GRID grid.417893.0, 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 ]GRID grid.414093.b, Pôle de Biologie, , Hôpital Européen Georges Pompidou, AP-HP, ; Paris, France
                [24 ]Department of Women’s and Children’s Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
                [25 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Genomic Medicine, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [26 ]GRID grid.1042.7, Present Address: Immunology Division, , The Walter and Eliza Hall Institute of Medical Research, ; Melbourne, VIC Australia
                Author information
                http://orcid.org/0000-0001-5788-6840
                http://orcid.org/0000-0002-9067-8557
                http://orcid.org/0000-0003-1231-8641
                http://orcid.org/0000-0002-7268-5905
                http://orcid.org/0000-0002-8322-475X
                http://orcid.org/0000-0003-3524-7858
                http://orcid.org/0000-0001-7098-7240
                http://orcid.org/0000-0002-9334-4405
                http://orcid.org/0000-0003-3438-7576
                Article
                224
                10.1038/s41422-019-0224-x
                6796942
                31481761
                0cedaf64-cff2-487e-b9c8-017398282a2c
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 5 March 2019
                : 5 August 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100006364, Institut National Du Cancer (French National Cancer Institute);
                Funded by: FundRef https://doi.org/10.13039/501100010466, Chancellerie des Universités de Paris;
                Funded by: FundRef https://doi.org/10.13039/501100001677, Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research);
                Funded by: FundRef https://doi.org/10.13039/501100004795, Institut Universitaire de France (IUF);
                Funded by: Fondation Carrefour, European Union Horizon 2020 Project Oncobiome, European Research Area Network on Cardiovascular diseases, PIA2- TORINO LUMIERE, Swiss Bridge Foundation, ISREC Foundation, LABEX OncoImmunology, LeDucq Foundation, Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), the SIRIC Cancer Research and Personalized Medicine (CARPEM)
                Funded by: FundRef https://doi.org/10.13039/501100004097, Fondation ARC pour la Recherche sur le Cancer (ARC Foundation for Cancer Research);
                Funded by: FundRef https://doi.org/10.13039/501100001184, Cure Cancer Australia Foundation (CCAF);
                Award ID: 1163990
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research);
                Award ID: 12182
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000925, Department of Health | National Health and Medical Research Council (NHMRC);
                Award ID: 1111469
                Award ID: 1078671
                Award ID: 1132519
                Award Recipient :
                Funded by: Italian Miinistry of Health through "Ricerca Corrente"
                Funded by: FundRef https://doi.org/10.13039/100007423, Lyda Hill Foundation;
                Funded by: FundRef https://doi.org/10.13039/100007552, AIM at Melanoma (AIM at Melanoma Foundation);
                Categories
                Article
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                © IBCB, SIBS, CAS 2019

                Cell biology
                tumour immunology,cancer microenvironment
                Cell biology
                tumour immunology, cancer microenvironment

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