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PD-1 Is a Regulator of NY-ESO-1-Specific CD8⁺ T Cell Expansion in Melanoma Patients¹

Julien Fourcade^*, Pavol Kudela^*, Zhaojun Sun^*, Hongmei Shen, Stephanie R. Land, Diana Lenzner, Philippe Guillaume^¶, Immanuel F. Luescher^¶, Cindy Sander^*, Soldano Ferrone^,, John M. Kirkwood^* and Hassane M. Zarour^2,*,

^* Department of Medicine and Division of Hematology/Oncology, Department of Surgery, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health/National Cancer Institute Grants CA90360 and CA112198 (to H.M.Z.) and a Cancer Research Institute grant (to H.M.Z.).

² Address correspondence and reprint requests to Dr. Hassane Zarour, Hillman Cancer Center, Research Pavilion, Suite 1.32a, 5117 Centre Avenue, Pittsburgh, PA 15213. E-mail address: zarourhm{at}upmc.edu

³ Abbreviations used in this paper: CGA, cancer-germline Ag; ECD, energy-coupled dye; Flu, influenza; IVS, in vitro stimulation; MFI, mean fluorescence intensity; PD-1, programmed death 1 receptor; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; tet, tetramer.