高分化神经内分泌胃肠胰肿瘤中循环免疫细胞的特征及其与Tie2/血管生成素水平的相关性：一项横断面分析

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

作者信息

Sesti F, Puliani G, Feola T, Campolo F, Sciarra F, Hasenmajer V, Lenzi A, Faggiano A, Isidori A M, Venneri M A, Giannetta E

机构信息

Department of Experimental Medicine Sapienza University of Rome, Rome, Italy.

Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

出版信息

Endocrine. 2023 Apr;80(1):221-230. doi: 10.1007/s12020-022-03257-8. Epub 2022 Dec 12.

DOI:10.1007/s12020-022-03257-8

PMID:36509928

Abstract

PURPOSE

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 cells (PBMCs) 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 subjects: 15 patients naïve to treatment, with histologically proven gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and 15 healthy controls, matched for age and sex. PBMCs 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 CD3CD56 natural killer (NK) cell count in NETs vs controls (p = 0.04). NK subset analysis showed a reduced relative count of CD56CD16 NK cells (p =0.002) in NETs vs controls. Patients with NET showed a higher percentage of CD14CD16 non-classical monocytes (p = 0.01), and a lower percentage of CD14CD16 intermediate monocytes (p = 0.04). A decrease in percentage (p = 0.004) of CD4 T-helper lymphocytes was found in NET patients. Evaluation of cellular and serum angiopoietin pathway mediators revealed in NET patients a higher relative count of Tie2-expressing monocytes (TEMs) (p < 0.001), and high levels of Ang-1 (p = 0.003) and Ang-2 (p = 0.002).

CONCLUSIONS

Patients with GEP-NET 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 TEMs and angiopoietins suggest a crosstalk between innate immunity and angiogenic pathways in NETs.

摘要

目的

免疫环境是理解神经内分泌肿瘤（NENs）行为的一种新的但探索较少的工具。据推测，免疫抑制的微环境会促进NENs的进展。在NENs仍有限的诊断治疗管理中，对循环白细胞和外周血单核细胞（PBMCs）亚群的缺失分析将开辟新的视角。

方法

进行了一项横断面病例对照初步研究，连续招募30名受试者：15例未经治疗的患者，经组织学证实患有胃肠胰（GEP）神经内分泌肿瘤（NETs），以及15名年龄和性别匹配的健康对照。通过流式细胞术研究PBMCs亚群。通过酶联免疫吸附测定（ELISA）评估可溶性Tie2（sTie2）、血管生成素-1（Ang-1）、血管生成素-2（Ang-2）。

结果

免疫细胞分析显示，NETs患者的CD3CD56自然杀伤（NK）细胞计数显著低于对照组（p = 0.04）。NK亚群分析显示，NETs患者中CD56CD16 NK细胞的相对计数低于对照组（p = 0.002）。NET患者的CD14CD16非经典单核细胞百分比更高（p = 0.01），而CD14CD16中间单核细胞百分比更低（p = 0.04）。NET患者中发现CD4辅助性T淋巴细胞百分比降低（p = 0.004）。对细胞和血清血管生成素途径介质的评估显示NET患者中表达Tie2单核细胞（TEMs）的相对计数更高（p < 0.001），以及Ang-1（p = 0.003）和Ang-2（p = 0.002）水平升高。