Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent

• Type of Material: Article
• Authors: Alice O. Kamphorst, Emory University; Andreas Wieland, Emory University; Tahseen Nasti, Emory University; Shu Yang, Emory University; Ruan Zhang, Massachusetts General Hospital; Daniel L. Barber, Emory University; Bogumila T. Konieczny, Emory University; Candace Z. Daugherty, Emory University; Lydia Koenig, Emory University; Ke Yu, Emory University
• Language: English
• Date: 2017-03-31
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Association for the Advancement of Science. All rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/science.aaf0683
• Title of Journal or Parent Work: Science
• ISSN: 0036-8075
• Volume: 355
• Issue: 6332
• Start Page: 1423
• End Page: 1427
• Grant/Funding Information: This work was supported by Merck pre-clinical grant 52507 (RA and AOK), and the National Institutes of Health grants R01 AI30048 (RA), P01 AI080192 (RA and GJF), P01 AI056299 (AHS, RA, GJF and BRB), P01 AI054456 (AHS), R01 AI089955 (GJF), R01 CA72669 (BRB), R01 AI037691 (LAT and RZ).
• Keywords: PD-1; CANCER; Science & Technology; BLOCKADE; COSTIMULATION; IMMUNITY; EFFECTOR; Science & Technology - Other Topics; CHRONIC VIRAL-INFECTION; MEMORY; Multidisciplinary Sciences; RESPONSES
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Biology, Virology

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 of mice. 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 CD28/B7 pathway in PD-1 therapy of cancer patients.