Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.
Thorac Cancer. 2021 Oct;12(20):2666-2679. doi: 10.1111/1759-7714.14102. Epub 2021 Aug 28.
Various drug-sensitivity markers have been reported to be associated with tumor progression and chemotherapy resistance. Detailed expression profiles of sensitivity markers for cytotoxic chemotherapy in pulmonary large cell neuroendocrine carcinoma (LCNEC) remain unclear. Herein, we aimed to clarify the correlation between the expression of drug-sensitivity markers and clinicopathological features, prognostic impact, and status of tumor immunity in patients with LCNEC.
We retrospectively analyzed the correlation between clinicopathological features and the expression of drug-sensitivity-related markers, including vascular endothelial growth factor 2 (VEGFR2), thymidylate synthase (TS), tubulin beta 3 class III (TUBB3), topoisomerase I (Topo-I), and Topo-II in 92 surgically resected LCNEC samples. Furthermore, we examined the prognostic significance of expression of these and their correlation with the immune cell status.
Overall, high expression of TS, TUBB3, VEGFR2, Topo-I, and Topo-II was detected in 50 (54%), 31 (34%), 23 (25%), 65 (71%), and 36 (39%) samples, respectively. Univariate and multivariate analyses revealed that advanced pathological T and N factors, positive lymphatic permeation, and Topo-II expression were independent unfavorable prognosticators for recurrence-free survival, and advanced pathological T and N factors, Topo-II positive expression, and TS positive expression were independent unfavorable prognosticators for overall survival. In terms of correlation with immune cell status, higher expression of VEGFR2 was closely linked to negative PD-L1 expression.
These findings suggest that elevated Topo-II and TS expression may contribute to poor outcomes through protumoral biology in patients with LCNEC, and elevated VEGFR2 expression might negatively impact tumor immune reactions in LCNEC.
已有报道称，各种药物敏感性标志物与肿瘤进展和化疗耐药有关。在肺大细胞神经内分泌癌（LCNEC）中，细胞毒性化疗药物敏感性标志物的详细表达谱尚不清楚。在此，我们旨在阐明药物敏感性标志物的表达与 LCNEC 患者的临床病理特征、预后影响以及肿瘤免疫状态之间的相关性。
我们回顾性分析了 92 例手术切除的 LCNEC 样本中药物敏感性相关标志物（包括血管内皮生长因子 2（VEGFR2）、胸苷酸合成酶（TS）、微管蛋白β 3 类（TUBB3）、拓扑异构酶 I（Topo-I）和拓扑异构酶 II）的表达与临床病理特征的相关性。此外，我们还研究了这些标志物表达的预后意义及其与免疫细胞状态的相关性。
总体而言，50（54%）、31（34%）、23（25%）、65（71%）和 36（39%）例样本中分别检测到 TS、TUBB3、VEGFR2、Topo-I 和 Topo-II 的高表达。单因素和多因素分析显示，病理 T 和 N 分期较晚、淋巴管浸润阳性和 Topo-II 表达阳性是无复发生存的独立不良预后因素，而病理 T 和 N 分期较晚、Topo-II 表达阳性和 TS 表达阳性是总生存的独立不良预后因素。在与免疫细胞状态的相关性方面，VEGFR2 的高表达与 PD-L1 表达阴性密切相关。
这些发现表明，在 LCNEC 患者中，Topo-II 和 TS 的高表达可能通过促进肿瘤发生的生物学机制导致不良预后，而 VEGFR2 的高表达可能会对 LCNEC 中的肿瘤免疫反应产生负面影响。
