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Science. 2017 Mar 31;355(6332):1423-1427. doi: 10.1126/science.aaf0683. Epub 2017 Mar 9.

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

Author information

1
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China, 410013.
3
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02144, USA.
4
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
5
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
6
Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
7
Department of Microbiology and Immunobiology and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Woman's Hospital, Boston, MA 02115, USA.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
9
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
10
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. rahmed@emory.edu.

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.

PMID:
28280249
PMCID:
PMC5595217
DOI:
10.1126/science.aaf0683
[Indexed for MEDLINE]
Free PMC Article

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