通过免疫微环境参数预测胃肠胰神经内分泌肿瘤（GEP-NETs）的镥-奥曲肽治疗反应。

Predicting Lu-DOTATATE therapy response through immune microenvironment parameters in gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

作者信息

Zeng Ziqing, Zhang Zizhen, Xie Qing, Tao Jinping, Zhou Wenyuan, Yuan Chunhui, Yang Zhi, Lu Ming, Yu Jiangyuan

机构信息

Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Research, Investigation and Evaluation of Radiopharmaceuticals, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng road, Haidian district, Beijing, 100142, China.

State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng road, Haidian district, Beijing, 100142, China.

出版信息

Eur J Nucl Med Mol Imaging. 2025 Aug 5. doi: 10.1007/s00259-025-07458-x.

DOI:10.1007/s00259-025-07458-x

PMID:40762799

Abstract

BACKGROUND

The prognosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) following metastasis is often poor. The efficacy of Lu-DOTATATE therapy and the subgroups that benefit from it remain unclear. Our objective is to characterize the composition of the tumor immune microenvironment in GEP-NETs and to identify predictive biomarkers associated with response and PFS following Lu-DOTATATE.

METHODS

Multiplex immunofluorescence (mIF) staining of tumor sections was used to characterize the cellular density and spatial organization of the microenvironment of 50 NET patients. The relationship between baseline immune microenvironment and Lu-DOTATATE efficacy or prognosis in 20 Lu-DOTATATE-treated patients was explored.

RESULTS

Patients with GEP-NET exhibited an immunosuppressive microenvironment. The overall response rate (ORR) to Lu-DOTATATE therapy was 60%. Patients with a good response (partial response or complete response) had a lower density of regulatory T cells (Tregs) and CD8TIM-3 cells at baseline, with greater nearest neighbor distances between Tregs and CD8 T cells, Tregs and CD11c dendritic cells (DCs), as well as Tregs and CD163 M2 macrophages. Conversely, patients with a poor response (stable disease or progressive disease) had greater distances between CD8 T cells and DCs, and more clustering pattern between CK tumor cells and CD8TIM-3 cells. Furthermore, a logistic regression-based predictive model for Lu-DOTATATE efficacy was established, which maintained good discrimination after internal validation. Finally, the study revealed that Counts-(CD163)(CD11c) positively correlated with progression-free survival (PFS) post-Lu-DOTATATE.

CONCLUSIONS

The immune microenvironment parameters of GEP-NET patients are closely associated with Lu-DOTATATE therapy efficacy. Our findings provide a potential tool for predicting Lu-DOTATATE efficacy and patient selection, offering direction for precision clinical strategies and potential combination therapies in GEP-NET.

摘要

背景

胃肠道胰腺神经内分泌肿瘤（GEP-NETs）发生转移后的预后通常较差。镥[177Lu]奥曲肽治疗的疗效以及从中获益的亚组尚不清楚。我们的目标是描述GEP-NETs中肿瘤免疫微环境的组成，并确定与镥[177Lu]奥曲肽治疗反应和无进展生存期（PFS）相关的预测生物标志物。

方法

采用肿瘤切片的多重免疫荧光（mIF）染色来描述50例神经内分泌肿瘤（NET）患者微环境的细胞密度和空间组织。探讨了20例接受镥[177Lu]奥曲肽治疗患者的基线免疫微环境与镥[177Lu]奥曲肽疗效或预后之间的关系。

结果

GEP-NET患者表现出免疫抑制微环境。镥[177Lu]奥曲肽治疗的总缓解率（ORR）为60%。反应良好（部分缓解或完全缓解）的患者在基线时调节性T细胞（Tregs）和CD8 TIM-3细胞的密度较低，Tregs与CD8 T细胞、Tregs与CD11c树突状细胞（DCs）以及Tregs与CD163 M2巨噬细胞之间的最近邻距离更大。相反，反应较差（疾病稳定或进展）的患者CD8 T细胞与DCs之间的距离更大，细胞角蛋白（CK）肿瘤细胞与CD8 TIM-3细胞之间的聚集模式更多。此外，建立了基于逻辑回归的镥[177Lu]奥曲肽疗效预测模型，该模型在内部验证后保持了良好的区分度。最后，研究表明计数-(CD163)(CD11c)与镥[177Lu]奥曲肽治疗后的无进展生存期（PFS）呈正相关。