{"title":"探索纳武单抗治疗不可切除/复发性食管鳞状细胞癌的疗效和生存率的预测性生物标志物。","authors":"Shigeto Nakai, Tomoki Makino, Kota Momose, Kotaro Yamashita, Koji Tanaka, Hiroshi Miyata, Sachiko Yamamoto, Masaaki Motoori, Yutaka Kimura, Ryohei Kawabata, Motohiro Hirao, Jin Matsuyama, Yusuke Akamaru, Hitomi Morihara, Azumi Ueyama, Yukinori Kurokawa, Eiichi Morii, Hisashi Wada, Hidetoshi Eguchi, Yuichiro Doki","doi":"10.1007/s10388-025-01120-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Programmed cell death protein-1 (PD-1) blockade has improved survival for patients with esophageal squamous cell carcinoma (ESCC), but response rates are low. Biomarkers to predict who will benefit from PD-1 blockade are urgently needed.</p><p><strong>Methods: </strong>This multicenter study involved 250 patients with recurrent/unresectable advanced ESCC receiving nivolumab as second- or later-line therapy. We assessed tumor-infiltrating T lymphocytes (TILs) and tertiary lymphoid structure (TLS) density using immunohistochemistry and hematoxylin/eosin staining in surgical specimens and pre-nivolumab endoscopic biopsies.</p><p><strong>Results: </strong>In surgical specimens, clinical response (vs. non-response) to nivolumab correlated significantly with CD8<sup>+</sup> lymphocyte count (160 vs. 95.2 cells/field, P = 0.0494), CD8/Foxp3 ratio (6.52 vs. 2.72, P = 0.0053), and TLS density (0.21/mm<sup>2</sup> vs. 0.10/mm<sup>2</sup>, P = 0.0005). In terms of overall survival, multivariate analysis identified CD8/Foxp3 ratio (hazard ratio [HR] = 1.83, P = 0.0050) and TLS density (HR = 1.67, P = 0.0171 as independent prognostic parameters in surgical specimens. Similarly, in endoscopic biopsies, clinical response (vs. non-response) to nivolumab correlated significantly with CD8<sup>+</sup> counts (254 cells/mm<sup>2</sup> vs. 124 cells/mm<sup>2</sup>, P = 0.0344), CCR8<sup>+</sup> lymphocyte count (62.6 cells/mm<sup>2</sup> vs. 140 cells/mm<sup>2</sup>, P = 0.0355), CD8/Foxp3 ratio (2.09 vs. 0.89, P = 0.040), and CD8/CCR8 ratio (2.34 vs. 0.89, P = 0.0020). Multivariate analysis also identified CD8/CCR8 ratio in endoscopic biopsies (HR = 1.66, P = 0.0313) as an independent prognostic parameter.</p><p><strong>Conclusions: </strong>CD8<sup>+</sup> and CCR8<sup>+</sup> cell counts, CD8/Foxp3 and CD8/CCR8 ratios, and TLS density may be predictive biomarkers of therapeutic efficacy and survival with PD-1 blockade for ESCC.</p>","PeriodicalId":11918,"journal":{"name":"Esophagus","volume":" ","pages":""},"PeriodicalIF":2.2000,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploring predictive biomarkers of efficacy and survival with nivolumab treatment for unresectable/recurrent esophageal squamous cell carcinoma.\",\"authors\":\"Shigeto Nakai, Tomoki Makino, Kota Momose, Kotaro Yamashita, Koji Tanaka, Hiroshi Miyata, Sachiko Yamamoto, Masaaki Motoori, Yutaka Kimura, Ryohei Kawabata, Motohiro Hirao, Jin Matsuyama, Yusuke Akamaru, Hitomi Morihara, Azumi Ueyama, Yukinori Kurokawa, Eiichi Morii, Hisashi Wada, Hidetoshi Eguchi, Yuichiro Doki\",\"doi\":\"10.1007/s10388-025-01120-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Programmed cell death protein-1 (PD-1) blockade has improved survival for patients with esophageal squamous cell carcinoma (ESCC), but response rates are low. Biomarkers to predict who will benefit from PD-1 blockade are urgently needed.</p><p><strong>Methods: </strong>This multicenter study involved 250 patients with recurrent/unresectable advanced ESCC receiving nivolumab as second- or later-line therapy. We assessed tumor-infiltrating T lymphocytes (TILs) and tertiary lymphoid structure (TLS) density using immunohistochemistry and hematoxylin/eosin staining in surgical specimens and pre-nivolumab endoscopic biopsies.</p><p><strong>Results: </strong>In surgical specimens, clinical response (vs. non-response) to nivolumab correlated significantly with CD8<sup>+</sup> lymphocyte count (160 vs. 95.2 cells/field, P = 0.0494), CD8/Foxp3 ratio (6.52 vs. 2.72, P = 0.0053), and TLS density (0.21/mm<sup>2</sup> vs. 0.10/mm<sup>2</sup>, P = 0.0005). In terms of overall survival, multivariate analysis identified CD8/Foxp3 ratio (hazard ratio [HR] = 1.83, P = 0.0050) and TLS density (HR = 1.67, P = 0.0171 as independent prognostic parameters in surgical specimens. Similarly, in endoscopic biopsies, clinical response (vs. non-response) to nivolumab correlated significantly with CD8<sup>+</sup> counts (254 cells/mm<sup>2</sup> vs. 124 cells/mm<sup>2</sup>, P = 0.0344), CCR8<sup>+</sup> lymphocyte count (62.6 cells/mm<sup>2</sup> vs. 140 cells/mm<sup>2</sup>, P = 0.0355), CD8/Foxp3 ratio (2.09 vs. 0.89, P = 0.040), and CD8/CCR8 ratio (2.34 vs. 0.89, P = 0.0020). 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引用次数: 0
摘要
背景：程序性细胞死亡蛋白-1 （PD-1）阻断可改善食管鳞状细胞癌（ESCC）患者的生存率，但应答率较低。目前迫切需要生物标志物来预测谁将从PD-1阻断中获益。方法：这项多中心研究纳入了250例复发/不可切除的晚期ESCC患者，他们接受纳武单抗作为二线或后期治疗。我们使用免疫组织化学和苏木精/伊红染色评估手术标本和纳武单抗前内镜活检的肿瘤浸润T淋巴细胞（TILs）和三级淋巴结构（TLS）密度。结果：在手术标本中，nivolumab的临床应答（vs.无应答）与CD8+淋巴细胞计数（160 vs. 95.2细胞/场，P = 0.0494）、CD8/Foxp3比值（6.52 vs. 2.72, P = 0.0053）和TLS密度（0.21/mm2 vs. 0.10/mm2, P = 0.0005）显著相关。在总生存率方面，多因素分析发现CD8/Foxp3比值（风险比[HR] = 1.83, P = 0.0050）和TLS密度（HR = 1.67, P = 0.0171）是手术标本的独立预后参数。同样，在内镜活检中，nivolumab的临床反应（vs.无反应）与CD8+计数（254个细胞/mm2 vs. 124个细胞/mm2， P = 0.0344）、CCR8+淋巴细胞计数（62.6个细胞/mm2 vs. 140个细胞/mm2， P = 0.0355）、CD8/Foxp3比值（2.09 vs. 0.89, P = 0.040）和CD8/CCR8比值（2.34 vs. 0.89, P = 0.0020）显著相关。多因素分析还发现，内镜活检中CD8/CCR8比值（HR = 1.66, P = 0.0313）是一个独立的预后参数。结论：CD8+和CCR8+细胞计数、CD8/Foxp3和CD8/CCR8比值以及TLS密度可能是PD-1阻断治疗ESCC的疗效和生存率的预测性生物标志物。
Exploring predictive biomarkers of efficacy and survival with nivolumab treatment for unresectable/recurrent esophageal squamous cell carcinoma.
Background: Programmed cell death protein-1 (PD-1) blockade has improved survival for patients with esophageal squamous cell carcinoma (ESCC), but response rates are low. Biomarkers to predict who will benefit from PD-1 blockade are urgently needed.
Methods: This multicenter study involved 250 patients with recurrent/unresectable advanced ESCC receiving nivolumab as second- or later-line therapy. We assessed tumor-infiltrating T lymphocytes (TILs) and tertiary lymphoid structure (TLS) density using immunohistochemistry and hematoxylin/eosin staining in surgical specimens and pre-nivolumab endoscopic biopsies.
Results: In surgical specimens, clinical response (vs. non-response) to nivolumab correlated significantly with CD8+ lymphocyte count (160 vs. 95.2 cells/field, P = 0.0494), CD8/Foxp3 ratio (6.52 vs. 2.72, P = 0.0053), and TLS density (0.21/mm2 vs. 0.10/mm2, P = 0.0005). In terms of overall survival, multivariate analysis identified CD8/Foxp3 ratio (hazard ratio [HR] = 1.83, P = 0.0050) and TLS density (HR = 1.67, P = 0.0171 as independent prognostic parameters in surgical specimens. Similarly, in endoscopic biopsies, clinical response (vs. non-response) to nivolumab correlated significantly with CD8+ counts (254 cells/mm2 vs. 124 cells/mm2, P = 0.0344), CCR8+ lymphocyte count (62.6 cells/mm2 vs. 140 cells/mm2, P = 0.0355), CD8/Foxp3 ratio (2.09 vs. 0.89, P = 0.040), and CD8/CCR8 ratio (2.34 vs. 0.89, P = 0.0020). Multivariate analysis also identified CD8/CCR8 ratio in endoscopic biopsies (HR = 1.66, P = 0.0313) as an independent prognostic parameter.
Conclusions: CD8+ and CCR8+ cell counts, CD8/Foxp3 and CD8/CCR8 ratios, and TLS density may be predictive biomarkers of therapeutic efficacy and survival with PD-1 blockade for ESCC.
期刊介绍：
Esophagus, the official journal of the Japan Esophageal Society, introduces practitioners and researchers to significant studies in the fields of benign and malignant diseases of the esophagus. The journal welcomes original articles, review articles, and short articles including technical notes ( How I do it ), which will be peer-reviewed by the editorial board. Letters to the editor are also welcome. Special articles on esophageal diseases will be provided by the editorial board, and proceedings of symposia and workshops will be included in special issues for the Annual Congress of the Society.
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