PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells.
Regulatory CD4(+)CD25(Hi) 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-gamma and IL-2 or INF-gamma and tumor necrosis factor-alpha 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.
Wang
Wenshi
W
Donald A Adam Comprehensive Melanoma Research Center, Department of Immunology and Immunotherapy, Moffitt Cancer Center, 12902 Magnolia Drive, SRB-24324, Tampa, FL 33612, USA. wenshi.wang@moffitt.org
Lau
Roy
R
Yu
Daohai
D
Zhu
Weiwei
W
Korman
Alan
A
Weber
Jeffrey
J
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D060890:B7-H1 Antigen; D015704:CD4 Antigens / Q000276:immunology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D009367:Neoplasm Staging; D061026:Programmed Cell Death 1 Receptor; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*
D000906:Antibodies; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor