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

• 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
• Journal Title: Science
• Volume: Volume 355, Number 6332
• Publisher: American Association for the Advancement of Science | 2017-03-31, Pages 1423-1427
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1126/science.aaf0683
• Subjects: Biology, Microbiology; Health Sciences, Immunology; Biology, Virology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; CHRONIC VIRAL-INFECTION; RESPONSES; IMMUNITY; CANCER; PD-1; COSTIMULATION; BLOCKADE; EFFECTOR; MEMORY

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.