Modulation of human tumor antigen-specific T cell responses by programmed death-1 blockade

UnrestrictedNegative costimulatory signaling mediated via cell surface Programmed Death-1 (PD-1) expression modulates T and B cell activation and is critical for maintaining peripheral tolerance. Abrogation of the PD-1 pathway may therefore be useful strategy to enhance the induction of antigen-specific T cells by vaccination. In these studies, we examined the effects of a fully human PD-1-abrogating antibody on the in vitro expansion and functional profile of human CD8+ T cells (CTLs) specific for the melanoma-associated antigens gp100 and MART-1. PD-1 blockade during peptide stimulation augmented the absolute numbers of CD3+, CD4+, CD8+, and MHC:peptide tetramer-binding CTLs. This correlated with increased frequencies of IFN-gamma-secreting antigen-specific cells and augmented lysis of peptide-pulsed targets as well as gp100+/MART+ melanoma cell lines. 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 primarily from augmented proliferation, and not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both Type-1 and Type-2 cytokine secretion, without any apparent skewing of the cytokine repertoire. PD-1 blockade did not significantly alter the phenotype of peptide-stimulated gp100- and MART-1-specific CTLs, which were predominantly activated effector / effector memory cells characterized by a CD45RA(low), CD45RO(high), CCR7(low), CD62L(low), and CD44(high), expression profile. Vaccine-induced gp100- and MART-1-specific memory CTLs were also found to be dependent on CD4+ T help for optimal expansion during in vitro peptide stimulation. These findings suggest that PD-1 blockade may augment CTL expansion directly and/or indirectly through the augmented provision of CD4+ T help.; These findings contribute to the basic understanding of human CTL expansion and have implications for developing new cancer immunotherapy strategies