Abstract
Natural killer (NK) cells are key effectors in cancer immunosurveillance and can be used as a prognostic biomarker in diverse cancers. Nonetheless, the role of NK cells in pancreatic cancer (PC) remains elusive, given conflicting data on their association with disease prognosis. In this study, using conventional K562 target cells and complementary engineered target cells providing defined and synergistic stimulation for NK cell activation, a correlation between impaired NK cell cytotoxic degranulation and PC progression was determined. Peripheral blood mononuclear cells (PBMCs) from 31 patients with newly diagnosed PC, 24 patients with non-malignant tumors, and 37 healthy controls were analyzed by flow cytometry. The frequency, phenotype, and effector functions of the NK cells were evaluated, and correlations between NK cell functions and disease stage and prognosis were analyzed. The results demonstrated that effector functions, but not frequency, of NK cells was progressively decreased on a per-cell basis during PC progression. Impaired cytotoxic degranulation, but not IFN-γ production, was associated with clinical features indicating disease progression, such as high serum CA19-9 and high-grade tumors. Significantly, this impairment correlated with cancer recurrence and mortality in a prospective analysis. Furthermore, the impaired cytotoxic degranulation was unrelated to NKG2D downregulation but was associated with increased circulating and tumor-associated TGF-β1 expression. Thus, NK cell cytotoxic activity was associated with PC progression and may be a favorable biomarker with predictive and prognostic value in PC.
Highlights
Pancreatic cancer (PC) is characterized by a remarkably poor prognosis with the lowest 5 year survival rate (∼7%) of all cancers [1]
In PC, less attention has been paid to Natural killer (NK) cells than other immune effector cells [42], and their therapeutic potential has only recently been appreciated [30]
Considering the high variability in NK cell frequencies among human patients [14], the conflicting observations in previous studies might be due to the use of methods that measure NK cell activity within bulk Peripheral blood mononuclear cells (PBMCs) preparations rather than the methods employed here, which measure NK cell activity on a per-cell basis
Summary
Pancreatic cancer (PC) is characterized by a remarkably poor prognosis with the lowest 5 year survival rate (∼7%) of all cancers [1]. Pancreatic ductal adenocarcinoma (PDAC) is the most common subtype (∼95%), and is typically identified with distant metastasis, the leading cause of PDAC-related death, due to the lack of early symptoms and predictive biomarkers [3, 4]. Therapeutic options are limited for PC, with only a minority of patients (∼15%) being eligible for surgical resection, the best curative treatment for non-disseminated disease. The outcome of early complete resection remains poor due to high recurrence rates (∼80%). Chemotherapy and targeted therapy for advanced-stage PC still have a limited impact on patient survival [5, 6]. It is important to identify additional and valid prognostic factors of PC progression to develop effective diagnostics and therapies
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