Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma.

Carcinogenesis / genetics Cell Line, Tumor Cyclin-Dependent Kinase 4 / antagonists & inhibitors Histone Deacetylase Inhibitors / therapeutic use Histone Deacetylases / genetics Humans Molecular Targeted Therapy Oncogene Proteins, Fusion / antagonists & inhibitors Oncogenes / genetics RNA-Seq Sarcoma, Synovial / drug therapy Single-Cell Analysis

Journal

Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015

Informations de publication

Date de publication:
02 2021
Historique:
received: 05 10 2019
accepted: 14 12 2020
pubmed: 27 1 2021
medline: 27 2 2021
entrez: 26 1 2021
Statut: ppublish

Résumé

Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.

Identifiants

DOI: 10.1038/s41591-020-01212-6 PMID: 33495604 PMC: PMC8817899
pubmed: 33495604
doi: 10.1038/s41591-020-01212-6
pii: 10.1038/s41591-020-01212-6
pmc: PMC8817899
mid: NIHMS1727124
doi:

Substances chimiques

Histone Deacetylase Inhibitors 0
Oncogene Proteins, Fusion 0
Cyclin-Dependent Kinase 4 EC 2.7.11.22
Histone Deacetylases EC 3.5.1.98

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

289-300

Subventions

Organisme : NCI NIH HHS
ID : U54 CA225088
Pays : United States
Organisme : Harvard Medical School
ID : CA225088
Organisme : NCI NIH HHS
ID : P30 CA014051
Pays : United States
Organisme : Burroughs Wellcome Fund (BWF)
ID : K08CA222663
Organisme : NCI NIH HHS
ID : R33 CA202820
Pays : United States
Organisme : Burroughs Wellcome Fund (BWF)
ID : 1019508
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : PP00P3-157468/1
Organisme : NCI NIH HHS
ID : R50 CA211461
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA180922
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA245523
Pays : United States
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : PP00P3_183724
Organisme : NCI NIH HHS
ID : K08 CA222663
Pays : United States
Organisme : Broad Institute
ID : R37CA245523
Organisme : NCI NIH HHS
ID : L30 CA231679
Pays : United States

Commentaires et corrections

Type : CommentIn

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Auteurs

Livnat Jerby-Arnon (L)

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Chan Zuckerberg Biohub, San Francisco, CA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
ORCID: 0000-0002-4037-386X

Cyril Neftel (C)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Marni E Shore (ME)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Hannah R Weisman (HR)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Nathan D Mathewson (ND)

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Immunology, Harvard Medical School, Boston, MA, USA.
Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
ORCID: 0000-0002-8895-2609

Matthew J McBride (MJ)

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Brian Haas (B)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Benjamin Izar (B)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Columbia Center for Translational Immunology, New York, NY, USA.
Columbia University Medical Center, Division of Hematology and Oncology, New York, NY, USA.
ORCID: 0000-0003-2379-6702

Angela Volorio (A)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Gaylor Boulay (G)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Luisa Cironi (L)

Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Alyssa R Richman (AR)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Liliane C Broye (LC)

Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Joseph M Gurski (JM)

Massachusetts General Hospital Cancer Center, Boston, MA, USA.
ORCID: 0000-0002-1668-3542

Christina C Luo (CC)

Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Ravindra Mylvaganam (R)

Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Lan Nguyen (L)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Shaolin Mei (S)

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

Johannes C Melms (JC)

Columbia Center for Translational Immunology, New York, NY, USA.
Columbia University Medical Center, Division of Hematology and Oncology, New York, NY, USA.

Christophe Georgescu (C)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Ofir Cohen (O)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Jorge E Buendia-Buendia (JE)

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Asa Segerstolpe (A)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Malika Sud (M)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Michael S Cuoco (MS)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA.
ORCID: 0000-0003-2163-5120

Danny Labes (D)

Flow Cytometry Facility, Department of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

Simon Gritsch (S)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Daniel R Zollinger (DR)

NanoString Technologies, Seattle, WA, USA.

Nicole Ortogero (N)

NanoString Technologies, Seattle, WA, USA.

Joseph M Beechem (JM)

NanoString Technologies, Seattle, WA, USA.

G Petur Nielsen (G)

Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Ivan Chebib (I)

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

Tu Nguyen-Ngoc (T)

Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.

Michael Montemurro (M)

Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.

Gregory M Cote (GM)

Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.

Edwin Choy (E)

Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0001-9896-8084

Igor Letovanec (I)

Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Stéphane Cherix (S)

Department of Orthopedics, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
ORCID: 0000-0001-5500-0508

Nikhil Wagle (N)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Peter K Sorger (PK)

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-3364-1838

Alex B Haynes (AB)

Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.

John T Mullen (JT)

Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.

Ivan Stamenkovic (I)

Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Miguel N Rivera (MN)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Cigall Kadoch (C)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-4058-5985

Kai W Wucherpfennig (KW)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Immunology, Harvard Medical School, Boston, MA, USA.

Orit Rozenblatt-Rosen (O)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Genentech, South San Francisco, CA, USA.
ORCID: 0000-0001-6313-3570

Mario L Suvà (ML)

Broad Institute of Harvard and MIT, Cambridge, MA, USA. Suva.Mario@mgh.harvard.edu.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. Suva.Mario@mgh.harvard.edu.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Suva.Mario@mgh.harvard.edu.
ORCID: 0000-0001-9898-5351

Nicolò Riggi (N)

Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. nicolo.riggi@chuv.ch.
Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. nicolo.riggi@chuv.ch.
ORCID: 0000-0001-9160-1984

Aviv Regev (A)

Broad Institute of Harvard and MIT, Cambridge, MA, USA. aregev@broadinstitute.org.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. aregev@broadinstitute.org.
Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA. aregev@broadinstitute.org.
Genentech, South San Francisco, CA, USA. aregev@broadinstitute.org.
ORCID: 0000-0003-3293-3158

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Classifications MeSH

questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Carcinogenèse › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Kinases cyclines-dépendantes › Kinase-4 cycline-dépendante › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de désacétylase d'histone › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Amidohydrolases › Histone deacetylases › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Thérapie moléculaire ciblée › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines de fusion oncogènes › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Gènes tumoraux › Oncogènes › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › RNA-Seq › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu conjonctif et des tissus mous › Sarcomes › Sarcome synovial › Opposing immune and genetic mechanisms shape...
questionsmedicales.fr › Techniques d'investigation › Techniques cytologiques › Analyse sur cellule unique › Opposing immune and genetic mechanisms shape...