Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Abstract

Background: Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods: We performed multiparametric cytofluorimetric analysis of PD-1 1 NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results: We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A 2 KIR 1 CD57 1 phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their

PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma

“…However, we found no correlation between PD-1 expression on NK cells and detectable HHV8 viremia, and observed only a weak correlation between the percentages of PD-1 pos NK cells and PD-1 pos CD8 T cells ( r = 0.28, P = 0.01). Recently, PD-1 pos NK cells were observed in healthy individuals seropositive for cytomegalovirus [40]. However, we found no association between PD-1 expression on NK cells and the presence of CMV-specific IgG in patients (mean PD-1 pos NK cells, 4% in CMV-positive and 3.8% in CMV-negative patients, p = 0.65).…”

“…Expression of Ki67, a nuclear protein associated with cell-cycle progression and generally used as a marker of recently divided cells, was not significantly different in PD-1 pos and PD-1 neg NK cells. At contrast with the NKG2A − KIR + CD57 + fully mature PD-1 pos NK cell population recently described in CMV-seropositive healthy controls [40], we found a similar proportion of PD-1 pos and PD-1 neg NK cells expressing CD57, a marker of CD56 dim late differentiation suggested to mark memory-like NK cells that have been expanded in response to infection [48]. We also analyzed expression of KLRG1, a marker of post-mature NK cells having undergone proliferation [49, 50].…”

Human NK Cell Subsets in Pregnancy and Disease: Toward a New Biological Complexity

“…PD-1 + NK cells are confined to the CD56 dim NK cell subset and are primarily composed by NKG2A − KIRs + LIR-1 + CD57 + NK cells with low levels of NCRs and high expression of CD16 and perforin/granzyme, indicating that PD-1 expression is confined to terminally differentiated NK cells. However, PD-1 + NK cells show a low cytolytic activity against tumor targets cells and are poor cytokines producers (35). …”

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance

“…Moreover, quite recently it has been detected that tumor cells result more attackable by a subset of human natural killer cells (Nk), expressing PD-1 higher levels rather than by T-cells, whence it follows the timeliness of referring to such intriguing detection to perform novel anti-tumor immunotherapy methods (23).…”

“…Among the dendritic cell-based vaccines, sipuleucel-T -that has been approved by FDA in 2010 to treat minimally symptomatic mCRPC patients -consists, indeed, of dendritic cells generated from autologous peripheral blood mononuclear cells loated with fusion immunostimulatory protein (adjuvant GM-CSF) containing the antigen PAP, as appropriate PCa target given that its expression increases proportionally to tumor progression and metastatic spread (4,12,23,(26)(27)(28).…”