B7-H6-mediated downregulation of NKp30 in NK cells contributes to ovarian carcinoma immune escape

Abstract

In this study the phenotype and function of tumor-associated NK cells from peritoneal fluids of a selected cohort of patients with seropapillary ovarian carcinoma were analyzed. In > 50% of these patients, the expression of the activating receptor NKp30 in tumor-associated NK cells was substantially reduced as compared to autologous peripheral blood (PB) NK cells. The impaired expression of this receptor was associated with the presence of one of its cellular ligands (B7-H6), which was detectable as a surface/cytosolic molecule in tumor cells and as a soluble molecule in the peritoneal fluid. NK cells from patients expressing this NKp30low phenotype displayed an impaired interferon-gamma (IFNγ) production and cytolytic function when tested against target cells expressing surface B7-H6. Our data also suggest that in these patients, the defective expression and function of NKp30 may be induced by the chronic engagement of this receptor by soluble B7-H6 or by tumor cells expressing this ligand. The impairment of NK cell functions described herein could represent a novel mechanism by which the tumor microenvironment may contribute to the escape from immune surveillance.

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

“…In addition, in given patients they were present in higher proportions in PF than in PB of the same patients (Fig 8, A and C). Although, as previously reported, 40 the size of the CD56 bright NK cell subsets was usually larger in PF NK cells compared with PB NK cells of the same patients, PD-1 1 NK cells were confined to the CD56 dim NK cell subset (Fig 8, B). Notably, the size of the PD-1 1 NK cell subsets detected in PB of the patients was slightly larger than in PBs of HDs (Fig 8, C).…”

“…40 PD-1 1 cells could be detected in the PB of the majority of these patients. In addition, in given patients they were present in higher proportions in PF than in PB of the same patients (Fig 8, A and C).…”

“…Isolation, culture of human leukocytes, and gate strategy Mononuclear cells were obtained from heparinized PB 39 and from PF of patients with ovarian carcinoma (after depletion of epithelial cell adhesion molecule [ESA] 1 and CD90 1 cells by using Magnetic Dynabeads Goat anti-Mouse IgG) 40 by means of density gradient centrifugation over Ficoll (Sigma, St Louis, Mo) and then resuspended in RPMI 1640 supplemented with 2 mmol/L glutamine, 50 mg/mL penicillin, 50 mg/mL streptomycin, and 10% heat-inactivated FCS (Societa Prodotti Antibiotici, Milano, Italy).…”

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

“…32,33,44 Increased amounts of soluble B7-H6 were found in sera of melanoma patients and in the peritoneal fluid of ovarian carcinoma patients. 47,49 Soluble BAG6/BAT3 was detected in sera of CLL patients and could modulate NKp30-mediated cytotoxicity. 50 Recently, Galectin-3 has been described as a soluble molecule released from tumor cells and capable of inhibiting NKp30-induced NK cell functions.…”

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

“…B7-H6-mediated downregulation of NKp30 in NK cells might therefore contribute to immune evasion in ovarian cancer. 30 Although this mechanism has not been investigated in breast cancer, it may well explain the clinical significance of increased B7-H6 expression in breast cancer, since B7-H6 is involved in the progression of human breast cancer and could function as a significant prognostic biomarker.…”