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International Immunology 2007 19(10):1223-1234; doi:10.1093/intimm/dxm091
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© The Author 2007. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press and The Japanese Society for Immunology are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org

Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs

Raymond M. Wong1,2,4, Ron R. Scotland1,2, Roy L. Lau1,2, Changyu Wang3, Alan J. Korman3, W. M. Kast1,2 and Jeffrey S. Weber1,2,5

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-{gamma}-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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