International Immunology Advance Access originally published online on August 3, 2009
International Immunology 2009 21(9):1065-1077; doi:10.1093/intimm/dxp072
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PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+CD25Hi regulatory T cells
1 Donald A Adam Comprehensive Melanoma Research Center, Department of Immunology and Immunotherapy, Moffitt Cancer Center, 12902 Magnolia Drive, SRB-24324, Tampa, FL 33612, USA
2 Department of Biostatistics, Moffitt Cancer Center, 12902 Magnolia Drive, MRC-263C, Tampa, FL 33612, USA
3 Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Room 6428, Los Angeles, CA 90033, USA
4 Medarex Incorporated, 521 Cottonwood Drive, Milpitas, CA 95035, USA
Correspondence to: W. Wang; E-mail: wenshi.wang{at}moffitt.org
Regulatory CD4+CD25Hi T cells (Treg) and programmed death-1 (PD-1) molecule have emerged as pivotal players in immune regulation. However, the underlying mechanisms by which they impact antigen-specific CD8+ immune responses in cancer patients and how they interact with each other under physiologic conditions remain unclear. Herein, we examined the relationship of PD-1 and its abrogation to the function of Treg in patients with melanoma using short-term in vitro assays to generate melanoma-specific T cells. We identified Treg in the circulation of vaccinated melanoma patients and detected PD-1 expression on vaccine-induced melanoma antigen-specific CTLs, as well as on and within Treg from patients’ peripheral blood. Programmed death ligand (PD-L) 1 expression was also detected on patients’ Treg. PD-1 blockade promoted the generation of melanoma antigen-specific CTLs and masked their inhibition by Treg. The mechanisms by which PD-1 blockade mediated immune enhancement included direct augmentation of melanoma antigen-specific CTL proliferation, heightening their resistance to inhibition by Treg and direct limitation of the inhibitory ability of Treg. PD-1 blockade reversed the increased expression of PD-1 and PD-L1 on melanoma antigen-specific CTL by Treg, rescued INF-
and IL-2 or INF- and tumor necrosis factor-
co-expression and expression of IL-7 receptor by melanoma antigen-specific CTL which were diminished by Treg. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Treg. These data suggest that PD-1 is importantly implicated in the regulation of Treg function in melanoma patients.
Keywords: anti-PD-1, CD4+CD25+ regulatory T cells (Treg), CTL, melanoma
Transmitting editor: H. Kikutani
Received 25 November 2008, accepted 3 July 2009.