Characterization of circulating immune cells and correlation with Tie2/Angiopoietins level in well differentiated neuroendocrine gastroenteropancreatic tumors: a cross-sectional analysis

Abstract

AbstractPurpose:The immune environment represents a new, but little explored, tool for understanding neuroendocrine neoplasms (NENs) behavior. An immunosuppressed microenvironment is hypothesized to promote NENs progression. A missing profiling of circulating leukocyte and peripheral blood mononuclear cell (PBMC) subpopulations would open new perspectives in the still limited diagnostic-therapeutic management of NENs.Methods: A cross-sectional case-control pilot study was performed recruiting 30 consecutive patients: 15 naïve to treatment, with histologically proven gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and 15 healthy controls (Ctrl), matched for age and sex. PBMC subpopulations were studied by flow cytometry. Soluble Tie2 (sTie2), Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2) were evaluated by ELISA.Results: Immune cell profiling revealed a significant lower CD3-CD56+ natural killer (NK) cell count in NETsversusCtrl (p=0.04). NK subset analysis showed a reduced relative count of CD56+CD16+ NK cells (p=0.002) in NETsversusCtrl. Patients with NET showed a higher percentage of CD14+CD16++non-classical monocytes (p=0.01), and a lower percentage of CD14+CD16+intermediate monocytes (p=0.04). A decrease in percentage (p=0.004) of CD4+ T-helper lymphocytes was found in NETs patients. Evaluation of cellular and serum angiopoietin pathway mediators revealed in NET patients a higher relative count of TEM (p<0.001), and high levels of Ang-1 (p=0.003) and Ang-2 (p=0.002).Conclusions: patients with GEP-NETs presented an immunosuppressed environment characterized by a low count of cytotoxic NK cells, a high count of anti-inflammatory non-classical monocytes, and a low count of T-helper lymphocytes. Higher levels of TEM and angiopoietins suggest a crosstalk between innate immunity and angiogenic pathways in NETs.