PD-1 Is a Regulator of NY-ESO-1-Specific CD8+ T Cell Expansion in Melanoma Patients1
The Journal of Immunology, 2009, 182: 5240-5249.
Copyright © 2009 by The American Association of Immunologists, Inc. doi:10.4049/jimmunol.0803245
Julien Fourcade*, Pavol Kudela*, Zhaojun Sun*, Hongmei Shen{dagger}, Stephanie R. Land{ddagger}, Diana Lenzner{ddagger}, Philippe Guillaume¶, Immanuel F. Luescher¶, Cindy Sander*, Soldano Ferrone{dagger},§, John M. Kirkwood* and Hassane M. Zarour2,*,§
* Department of Medicine and Division of Hematology/Oncology, {dagger} Department of Surgery, {ddagger} Department of Biostatistics, Graduate School of Public Health, and § Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213; and ¶ Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland
The programmed death 1 (PD-1) receptor is a negative regulator of activated T cells and is up-regulated on exhausted virus-specific CD8+ T cells in chronically infected mice and humans. Programmed death ligand 1 (PD-L1) is expressed by multiple tumors, and its interaction with PD-1 resulted in tumor escape in experimental models. To investigate the role of PD-1 in impairing spontaneous tumor Ag-specific CD8+ T cells in melanoma patients, we have examined the effect of PD-1 expression on ex vivo detectable CD8+ T cells specific to the tumor Ag NY-ESO-1. In contrast to EBV, influenza, or Melan-A/MART-1-specific CD8+ T cells, NY-ESO-1-specific CD8+ T cells up-regulated PD-1 expression. PD-1 up-regulation on spontaneous NY-ESO-1-specific CD8+ T cells occurs along with T cell activation and is not directly associated with an inability to produce cytokines. Importantly, blockade of the PD-1/PD-L1 pathway in combination with prolonged Ag stimulation with PD-L1+ APCs or melanoma cells augmented the number of cytokine-producing, proliferating, and total NY-ESO-1-specific CD8+ T cells. Collectively, our findings support the role of PD-1 as a regulator of NY-ESO-1-specific CD8+ T cell expansion in the context of chronic Ag stimulation. They further support the use of PD-1/PD-L1 pathway blockade in cancer patients to partially restore NY-ESO-1-specific CD8+ T cell numbers and functions, increasing the likelihood of tumor regression. |
