Department of General Surgery, The Cancer Center, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China.
Sci Rep. 2024 Oct 21;14(1):24669. doi: 10.1038/s41598-024-75882-4.
Pancreatic neuroendocrine neoplasms (Pan-NEN) represent a group of highly heterogeneous cancers, characterized by complex and diverse biological behavior. The objective of this study was to systematically investigate the immunological features of the tumor microenvironment (TME) in Pan-NEN, aiming to identify prognostic biomarkers and explore the therapeutic potential of immunotherapy for Pan-NEN. Tumor and adjacent normal tissues were collected from 56 patients with Pan-NEN. Immunohistochemical analysis was conducted on tumor tissues using a panel of monoclonal antibodies targeting key immune markers. The expression levels of these markers were quantitatively assessed and correlated with clinicopathological features and overall survival. Low expression of CD3, CD8, CD4, CD68, CD163, Foxp3, CD56, CD69, GZMB, HLA-1, HLA-II, PD-1, and PD-L1 were observed in the majority of Pan-NEN patient samples. PD-1 expression was positively correlated with CD4 and Foxp3 expression, while PD-L1 expression was positively correlated with CD68, CD163, and Foxp3 expression; HLA-II expression was positively correlated with GZMB expression. Infiltration of lymphocytes (CD3 + or CD8+) and macrophages (CD68 + or CD163+) and expression of PD-1/PD-L1 were more pronounced in poorly differentiated neuroendocrine carcinoma (Pan-NEC) compared to well-differentiated neuroendocrine tumors (Pan-NET), while CD68 and PD-L1 correlated with advanced disease stage. Conversely, HLA-I antigen expression was commonly downregulated in Pan-NEC. Univariate Cox proportional hazard analysis demonstrated that tumor grade, stage; CD4+, CD68+, and CD163 + cell count; and expression of PD-1 and PD-L1 were significantly associated with poor survival outcomes, while the positive expression of HLA-I was correlated with a more favorable survival prognosis. Furthermore, multivariate Cox proportional hazard analyses revealed that tumor grade, stage, and PD-1 expression are independent prognostic factors. The immunological landscape of Pan-NEN offers potential prognostic value and therapeutic targets. The findings suggest that immunotherapy, particularly targeting the PD-1/PD-L1 pathway, may serve as a promising strategy for the treatment of Pan-NEN, especially for Pan-NEC patients.
胰腺神经内分泌肿瘤（Pan-NEN）是一组具有高度异质性的癌症，其生物学行为复杂多样。本研究旨在系统研究 Pan-NEN 肿瘤微环境（TME）的免疫学特征，旨在鉴定预后生物标志物并探索 Pan-NEN 的免疫治疗潜力。从 56 名 Pan-NEN 患者中收集肿瘤和相邻正常组织。使用针对关键免疫标志物的单克隆抗体组合对肿瘤组织进行免疫组织化学分析。定量评估这些标志物的表达水平，并与临床病理特征和总生存期相关联。在大多数 Pan-NEN 患者样本中观察到 CD3、CD8、CD4、CD68、CD163、Foxp3、CD56、CD69、GZMB、HLA-1、HLA-II、PD-1 和 PD-L1 的低表达。PD-1 表达与 CD4 和 Foxp3 表达呈正相关，而 PD-L1 表达与 CD68、CD163 和 Foxp3 表达呈正相关；HLA-II 表达与 GZMB 表达呈正相关。与分化良好的神经内分泌肿瘤（Pan-NET）相比，低分化神经内分泌癌（Pan-NEC）中淋巴细胞（CD3+或 CD8+）和巨噬细胞（CD68+或 CD163+）的浸润和 PD-1/PD-L1 的表达更为明显，而 CD68 和 PD-L1 与晚期疾病阶段相关。相反，HLA-I 抗原表达在 Pan-NEC 中普遍下调。单因素 Cox 比例风险分析表明，肿瘤分级、分期；CD4+、CD68+和 CD163+细胞计数；以及 PD-1 和 PD-L1 的表达与不良生存结局显著相关，而 HLA-I 的阳性表达与更有利的生存预后相关。此外，多因素 Cox 比例风险分析表明，肿瘤分级、分期和 PD-1 表达是独立的预后因素。Pan-NEN 的免疫学特征提供了潜在的预后价值和治疗靶点。研究结果表明，免疫治疗，特别是针对 PD-1/PD-L1 通路的免疫治疗，可能成为治疗 Pan-NEN 的一种有前途的策略，特别是对于 Pan-NEC 患者。
