title: Coinhibitory Pathways in Immunotherapy for Cancer.
abstract: The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.|Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts 02115.|Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Baumeister
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.|Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.|Novartis Institutes for BioMedical Research, Exploratory Immuno-oncology, Cambridge, Massachusetts 02139.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Department of Microbiology and Immunobiology, and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, Massachusetts 02115; email: arlene_sharpe@hms.harvard.edu.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D008213:Lymphocyte Activation / Q000187:drug effects; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: CTLA-4; PD-1; PD-L1; cancer immunotherapy; tumor immunity