title: PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity.
abstract: It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1-deleted MC38 cells in vivo,demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.|Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Vikram R
authors.initials: VR
authors.lastname: Juneja
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.|Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: McGuire
authors.affiliation: Division of Medical Sciences, Harvard Medical School, Boston, MA 02115.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Manguso
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.|Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: Martin W
authors.initials: MW
authors.lastname: LaFleur
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02115.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Natalie
authors.identifier: 0000-0003-2980-9244
authors.initials: N
authors.lastname: Collins
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02115.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: Gordon J
authors.identifier: 0000-0002-7210-5616
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 arlene_sharpe@hms.harvard.edu.|Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Arlene H
authors.identifier: 0000-0002-9736-2109
authors.initials: AH
authors.lastname: Sharpe
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor