PO.CL12.01 · 临床研究

NEUROD1阳性及合并YAP1主导型肺神经内分泌癌中ZEB1的表达与局部免疫抑制微环境相关

ZEB1 expression in NEUROD1-positive and combined YAP1-dominant pulmonary neuroendocrine carcinomas is associated with a locally immunosuppressive microenvironment

编号 3878 展板 11 时间 4/20 02:00–05:00 区域 Section 46 主讲 Noriko Takemura-Kobayashi, MD

分会场 Molecular Classification and Tumor Biology in Cancer

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作者与单位 Authors & Affiliations

Noriko Takemura-Kobayashi¹, Kei Asayama¹, Rawya Mohamed Salih Ibrahim¹, Masahiro Maki¹, Ryota Matsuoka¹, Aya Shiba-Ishii¹, Ayako Suzuki², Yutaka Suzuki², Daisuke Matsubara¹

¹Department of Diagnostic Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan,²Department of Computational Biology and Medical Sciences, the University of Tokyo, Chiba, Japan

摘要 Abstract

中文摘要

背景：肺神经内分泌癌（pNECs）包括小细胞肺癌（SCLC）和大细胞神经内分泌癌（LCNEC），根据ASCL1、NEUROD1、POU2F3和YAP1的表达可分为四种分子亚型。在非小细胞肺癌中，锌指E-box结合同源框1（ZEB1）作为上皮-间质转化（EMT）的关键调控因子，在低分化癌（大细胞癌和多形性癌）中的表达频率高于腺癌和鳞状细胞癌。癌细胞中ZEB1的表达与CD8+ T细胞减少及PD-L1介导的免疫抑制相关。然而，ZEB1阳性SCLC/LCNEC的特征尚不明确。目的：我们研究了ZEB1在pNECs中的表达及其与肿瘤微环境的关系。方法：对pNEC细胞系（13例SCLC和1例LCNEC：8例ASCL1主导型、3例NEUROD1主导型、1例POU2F3主导型和2例YAP1主导型）进行Western印迹分析。对手术切除标本（33例SCLC和46例LCNEC）进行免疫组化。对1例ZEB1阳性SCLC标本进行空间转录组分析。结果：使用pNEC细胞系的Western印迹显示，NEUROD1主导型和YAP1主导型细胞系呈EMT样表型（ZEB1高表达、E-cadherin缺失）。Vimentin在NEUROD1主导型细胞系中缺失，但在YAP1主导型细胞系中存在。ASCL1主导型和POU2F3主导型细胞系大多呈上皮性（ZEB1低表达/缺失、E-cadherin保留），尽管部分ASCL1主导型细胞系表达ZEB1。在ZEB1阳性ASCL1主导型细胞系（H2081）的异种移植瘤中，ZEB1与E-cadherin的表达相互排斥；ZEB1阳性区域为NEUROD1阳性，而ZEB1阴性区域为ASCL1阳性。对手术切除标本全切片的免疫组化显示，大多数ZEB1阳性pNECs为NEUROD1阳性或合并YAP1主导型病例（合并腺癌或鳞状细胞癌），呈局灶性ZEB1表达，而POU2F3主导型病例中ZEB1低表达或不表达。Vimentin在少数合并YAP1主导型pNECs中高表达，但在大多数病例中呈阴性。在同一病例中，ZEB1阳性区域较ZEB1阴性区域的CD3+和CD8+ T细胞浸润显著减少，且在空间转录组分析中肿瘤相关巨噬细胞（TAMs）浸润增加。结论：在NEUROD1阳性和合并YAP1主导型肺神经内分泌癌中观察到ZEB1的局灶性表达。ZEB1阳性区域CD3+和CD8+ T细胞匮乏而TAMs富集，提示ZEB1介导的EMT与局部免疫抑制微环境相关。

查看英文原文 English abstract

Background: Pulmonary neuroendocrine carcinomas (pNECs), comprising small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), are classified into four molecular subtypes based on the expression of ASCL1, NEUROD1, POU2F3, and YAP1. In non-small cell lung cancer, Zinc finger E-box binding homeobox 1 (ZEB1), a key regulator of epithelial-mesenchymal transition (EMT), is more frequently expressed in poorly differentiated carcinoma (large cell and pleomorphic carcinoma) than in adenocarcinoma and squamous cell carcinoma. ZEB1 expression in cancer cells is linked to the decreased CD8+ T-cells and PD-L1 mediated immunosuppression. However, the features of ZEB1-positive SCLC/LCNEC are poorly understood. Aim: We investigated the expression of ZEB1 in pNECs and its association with tumor microenvironment.Methods: Western blotting was performed on pNEC cell lines (13 SCLC and 1 LCNEC: 8 ASCL1-dominant, 3 NEUROD1-dominant, 1 POU2F3-dominant, and 2 YAP1-domiant). Immunohistochemistry was conducted on surgically resected samples (33 SCLC and 46 LCNEC). Spatial transcriptome analysis was performed on one ZEB1-positive SCLC sample. Results: Western blotting using pNEC cell lines showed EMT-like phenotype in NEUROD1- and YAP1-dominant cell lines (high ZEB1, E-cadherin loss). Vimentin was absent in NEUROD1-dominant but present in YAP1-dominant cell lines. ASCL1- and POU2F3-dominant cell lines were largely epithelial (low/absent ZEB1, E-cadherin retained), although a part of ASCL1-dominant cell lines expressed ZEB1. In the xenograft from a ZEB1-positive ASCL1-dominant cell line (H2081), the expression of ZEB1 and E-cadherin was mutually exclusive; ZEB1-positive area was NEUROD1-positve, whereas ZEB1-negative area was ASCL1-positive. Immunohistochemistry on whole-slide sections from surgically resected samples revealed that most ZEB1-positive pNECs were NEUROD1-positive or combined YAP1-dominant cases (combined with adenocarcinoma or squamous cell carcinoma), with localized ZEB1 expression, whereas POU2F3-dominant cases showed low or no expression of ZEB1. Vimentin was highly expressed in a few combined YAP1-dominant pNECs but negative in most cases. The ZEB1-positive area exhibited significantly reduced CD3+ and CD8+ T cells infiltration and, in spatial transcriptome analysis, increased tumor-associated macrophages (TAMs) infiltration than in the ZEB1-negative area in the same cases. Conclusion: Focal expression of ZEB1 was observed in NEUROD1-positive and combined YAP1-dominant pulmonary neuroendocrine carcinomas. ZEB1-positive area was poor in CD3+ and CD8+ T cells and enriched in TAMs, suggesting that ZEB1-mediated EMT is associated with a locally immunosuppressive microenvironment.

利益披露 Disclosure

N. Takemura-Kobayashi, None.. K. Asayama, None.. R. M. S. Ibrahim, None.. M. Maki, None.. R. Matsuoka, None.. A. Shiba-Ishii, None.. A. Suzuki, None. Y. Suzuki, DAIICHI SANKYO COMPANY, LIMITED ). FUJIFILM Corporation ). D. Matsubara, None.

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