Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs.
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.
Wong
Raymond M
RM
Department of Medicine, University of Southern California, 1441 Eastlake Avenue, Room 6428, Los Angeles, CA 90033, USA.
Scotland
Ron R
RR
Lau
Roy L
RL
Wang
Changyu
C
Korman
Alan J
AJ
Kast
W M
WM
Weber
Jeffrey S
JS
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D012878:Skin Neoplasms / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D058951:gp100 Melanoma Antigen
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; C548637:PMEL protein, human; D061026:Programmed Cell Death 1 Receptor; D058951:gp100 Melanoma Antigen