title: Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent.
abstract: Programmed cell death-1 (PD-1)-targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Alice O
authors.identifier: 0000-0002-9230-9501
authors.initials: AO
authors.lastname: Kamphorst
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Andreas
authors.identifier: 0000-0001-9648-7922
authors.initials: A
authors.lastname: Wieland
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Tahseen
authors.identifier: 0000-0002-5650-1563
authors.initials: T
authors.lastname: Nasti
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.|Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China, 410013.
authors.forename: Shu
authors.identifier: 0000-0003-2864-9971
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02144, USA.
authors.forename: Ruan
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.|Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Bogumila T
authors.initials: BT
authors.lastname: Konieczny
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Candace Z
authors.initials: CZ
authors.lastname: Daugherty
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Koenig
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.affiliation: Department of Microbiology and Immunobiology and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Woman's Hospital, Boston, MA 02115, USA.
authors.forename: Arlene H
authors.identifier: 0000-0002-9736-2109
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Gordon J
authors.identifier: 0000-0002-7210-5616
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Bruce R
authors.identifier: 0000-0002-9608-9841
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02144, USA.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Rathi N
authors.initials: RN
authors.lastname: Pillai
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. rahmed@emory.edu.
authors.forename: Rafi
authors.identifier: 0000-0002-9591-2621
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D017353:Gene Deletion; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000628:therapy*; D008216:Lymphocytic Choriomeningitis / Q000628:therapy*; D053858:Metabolic Networks and Pathways; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*
chemical_list: D018122:B7-1 Antigen; D018106:CD28 Antigens; D061026:Programmed Cell Death 1 Receptor