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Jerby-Arnon L, Neftel C, Shore ME, Weisman HR, Mathewson ND, McBride MJ, Haas B, Izar B, Volorio A, Boulay G, Cironi L, Richman AR, Broye LC, Gurski JM, Luo CC, Mylvaganam R, Nguyen L, Mei S, Melms JC, Georgescu C, Cohen O, Buendia-Buendia JE, Segerstolpe A, Sud M, Cuoco MS, Labes D, Gritsch S, Zollinger DR, Ortogero N, Beechem JM, Petur Nielsen G, Chebib I, Nguyen-Ngoc T, Montemurro M, Cote GM, Choy E, Letovanec I, Cherix S, Wagle N, Sorger PK, Haynes AB, Mullen JT, Stamenkovic I, Rivera MN, Kadoch C, Wucherpfennig KW, Rozenblatt-Rosen O, Suvà ML, Riggi N, Regev A. Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma. Nat Med 2021; 27:289-300. [PMID: 33495604 PMCID: PMC8817899 DOI: 10.1038/s41591-020-01212-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 12/14/2020] [Indexed: 11/08/2022]
Abstract
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.
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Affiliation(s)
- Livnat Jerby-Arnon
- 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
| | - Cyril Neftel
- 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
- 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
- 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
- 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
| | - Matthew J McBride
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Brian Haas
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Benjamin Izar
- 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
| | - Angela Volorio
- 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
- 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
- Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Alyssa R Richman
- 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
- Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Joseph M Gurski
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Christina C Luo
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ravindra Mylvaganam
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lan Nguyen
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Shaolin Mei
- Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Johannes C Melms
- Columbia Center for Translational Immunology, New York, NY, USA
- Columbia University Medical Center, Division of Hematology and Oncology, New York, NY, USA
| | | | - Ofir Cohen
- 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
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | | | - Malika Sud
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Michael S Cuoco
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA
| | - Danny Labes
- Flow Cytometry Facility, Department of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Simon Gritsch
- 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
| | | | | | | | - G Petur Nielsen
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ivan Chebib
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Tu Nguyen-Ngoc
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Michael Montemurro
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Gregory M Cote
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Edwin Choy
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Igor Letovanec
- Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Stéphane Cherix
- Department of Orthopedics, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Nikhil Wagle
- 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
- Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Alex B Haynes
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - John T Mullen
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Ivan Stamenkovic
- Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Miguel N Rivera
- 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
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Kai W Wucherpfennig
- 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
- 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
| | - Mario L Suvà
- 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.
| | - Nicolò Riggi
- 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.
| | - Aviv Regev
- Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA.
- Genentech, South San Francisco, CA, USA.
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Godefroy E, Wang Y, Souleimanian NE, Scotto L, Stevanovic S, Chen YT, Valmori D, Ayyoub M. Assessment of CD4+ T cells specific for the tumor antigen SSX-1 in cancer-free individuals. Cancer Immunol Immunother 2007; 56:1183-92. [PMID: 17186289 PMCID: PMC11030208 DOI: 10.1007/s00262-006-0269-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2006] [Accepted: 11/27/2006] [Indexed: 10/23/2022]
Abstract
Proteins encoded by genes of the SSX family are specifically expressed in tumors and are therefore relevant targets for cancer immunotherapy. One of the first identified family members, SSX-1, is expressed in a large fraction of synovial sarcomas as a fusion protein together with the product of the SYT gene. In addition, the full-length SSX-1 antigen is frequently expressed in tumors of several other histological types such as sarcoma, melanoma, hepatocellular carcinoma, ovarian cancer and myeloma. To date, however, SSX-1 specific T cell responses have not been investigated and no SSX-1 derived T cell epitopes have been described. Here, we have assessed the presence of CD4(+) T cells directed against the SSX-1 antigen in circulating lymphocytes of cancer-free individuals. After a single in vitro stimulation with a pool of peptides spanning the entire SSX-1 protein we could detect and isolate SSX-1-specific CD4(+) T cells from 5/5 donors analyzed. SSX-1-specific polyclonal populations isolated from these cultures recognized peptides located in three distinct regions of the protein containing clusters of sequences with significant predicted binding to frequently expressed MHC class II alleles. Characterization of specific clonal CD4(+) T cell populations derived from one donor allowed the identification of several naturally processed epitopes recognized in association with HLA-DR. These data document the existence of a significant repertoire of CD4(+) T cells specific for SSX-1 derived sequences in circulating lymphocytes of any individual that can be exploited for the development of both passive and active immunotherapeutic approaches to control disease evolution in cancer patients.
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Affiliation(s)
- Emmanuelle Godefroy
- Ludwig Institute Clinical Trial Center, Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building Room 20-07, New York, NY 10032 USA
| | - Yu Wang
- Ludwig Institute Clinical Trial Center, Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building Room 20-07, New York, NY 10032 USA
| | - Naira E. Souleimanian
- Ludwig Institute Clinical Trial Center, Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building Room 20-07, New York, NY 10032 USA
| | - Luigi Scotto
- Ludwig Institute Clinical Trial Center, Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building Room 20-07, New York, NY 10032 USA
| | - Stefan Stevanovic
- Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany
| | - Yao-Tseng Chen
- Department of Pathology, Weill Medical College of Cornell University, New York, NY USA
| | - Danila Valmori
- Ludwig Institute Clinical Trial Center, Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building Room 20-07, New York, NY 10032 USA
| | - Maha Ayyoub
- Ludwig Institute Clinical Trial Center, Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building Room 20-07, New York, NY 10032 USA
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