Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs
1 Department of Medicine
2 Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Room 6428, Los Angeles, CA 90033, USA
3 Medarex Incorporated, 521 Cottonwood Drive, Milpitas, CA 95035, USA
4 Present address: Department of Immunology, MannKind Corporation, 28903 North Avenue Paine, Valencia, CA 91355, USA
5 Present address: Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, SRB 22045, Tampa, FL 33612, USA
Correspondence to: J. Weber; E-mail: Jeffrey.weber{at}moffit.org
Negative co-stimulatory signaling mediated via cell surface programmed death (PD)-1 expression modulates T and B cell activation and is involved in maintaining peripheral tolerance. In this study, we examined the effects of a fully human PD-1-abrogating antibody on the in vitro expansion and function of human vaccine-induced CD8+ T cells (CTLs) specific for the melanoma-associated antigens glycoprotein 100 (gp100) and melanoma antigen recognized by T cells (MART)-1. PD-1 blockade during peptide stimulation augmented the absolute numbers of CD3+, CD4+, CD8+ and gp100/MART-1 MHC:peptide tetramer+ CTLs. This correlated with increased frequencies of IFN-
-secreting antigen-specific cells and augmented lysis of gp100+/MART-1+ melanoma targets. PD-1 blockade also increased the fraction of antigen-specific CTLs that recognized melanoma targets by degranulation, suggesting increased recognition efficiency for cognate peptide. The increased frequencies and absolute numbers of antigen-specific CTLs by PD-1 blockade resulted from augmented proliferation, not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both type-1 and type-2 cytokine accumulation in culture without any apparent skewing of the cytokine repertoire. These findings have implications for developing new cancer immunotherapy strategies.
Keywords: cancer, co-stimulation, immunotherapy, lymphocyte, vaccine
Transmitting editor: P. Ohashi
The upper right panel in Figure 3 has been corrected to read Absolute Number CD8+
Received 23 January 2007, accepted 20 July 2007.
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