title: Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.
abstract: The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Gubin
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Institute of Cell Biology, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Schuster
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Etienne
authors.initials: E
authors.lastname: Caron
authors.affiliation: 1] Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [2] Department of Medicine, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Ward
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Takuro
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ivanova
authors.affiliation: The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA.
authors.forename: Jasreet
authors.initials: J
authors.lastname: Hundal
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Cora D
authors.initials: CD
authors.lastname: Arthur
authors.affiliation: ISA Therapeutics B.V., 2333 CH Leiden, The Netherlands.
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Krebber
authors.affiliation: ISA Therapeutics B.V., 2333 CH Leiden, The Netherlands.
authors.forename: Gwenn E
authors.initials: GE
authors.lastname: Mulder
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Mireille
authors.initials: M
authors.lastname: Toebes
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Vesely
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Samuel S K
authors.initials: SS
authors.lastname: Lam
authors.affiliation: Bristol-Myers Squibb, 700 Bay Road, Redwood City, California 94063, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Pearce
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: 1] Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland [2] Faculty of Science, University of Zurich, Zurich, 8093 Zurich, Switzerland.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.affiliation: Department of Immunology, Institute of Cell Biology, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.affiliation: 1] ISA Therapeutics B.V., 2333 CH Leiden, The Netherlands [2] Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, The Netherlands.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: 1] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA [2] Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Gillanders
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D059447:Cell Cycle Checkpoints / Q000276:immunology*; D000939:Epitopes / Q000235:genetics; D007167:Immunotherapy; D008297:Male; D051379:Mice; D012509:Sarcoma / Q000276:immunology / Q000628:therapy*; D014614:Vaccines, Synthetic / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D014614:Vaccines, Synthetic