Exploring predictive biomarkers of efficacy and survival with nivolumab treatment for unresectable/recurrent esophageal squamous cell carcinoma

Nakai, Shigeto; Makino, Tomoki; Momose, Kota; Yamashita, Kotaro; Tanaka, Koji; Miyata, Hiroshi; Yamamoto, Sachiko; Motoori, Masaaki; Kimura, Yutaka; Kawabata, Ryohei; Hirao, Motohiro; Matsuyama, Jin; Akamaru, Yusuke; Morihara, Hitomi; Ueyama, Azumi; Kurokawa, Yukinori; Morii, Eiichi; Wada, Hisashi; Eguchi, Hidetoshi; Doki, Yuichiro

doi:https://doi.org/10.1007/s10388-025-01120-z

Exploring predictive biomarkers of efficacy and survival with nivolumab treatment for unresectable/recurrent esophageal squamous cell carcinoma

Nakai, Shigeto; Makino, Tomoki; Momose, Kota et al.

Esophagus, 2025

Number of Access:968（2025-07-18 12:32 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/101407

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Title	Exploring predictive biomarkers of efficacy and survival with nivolumab treatment for unresectable/recurrent esophageal squamous cell carcinoma
Creator	CreatorName Nakai, Shigeto
	NRID 1000080528620 1000080528620 researchmap permalink _-_-_- _-_-_- Scopus Author ID 56339970700 56339970700 CreatorName Makino, Tomoki
	NRID 1000050749752 1000050749752 researchmap permalink kom2005 kom2005 CreatorName Momose, Kota
	NRID 1000020747159 1000020747159 researchmap permalink k-yamashita k-yamashita Scopus Author ID 57191498316 57191498316 CreatorName Yamashita, Kotaro
	NRID 1000070621019 1000070621019 ORCID 0000-0001-5178-9388 0000-0001-5178-9388 researchmap permalink koji_tanaka koji_tanaka Scopus Author ID 55628548952 55628548952 CreatorName Tanaka, Koji
	NRID 1000080362713 1000080362713 CreatorName Miyata, Hiroshi
	CreatorName Yamamoto, Sachiko
	CreatorName Motoori, Masaaki
	NRID 1000080716994 1000080716994 CreatorName Kimura, Yutaka
	CreatorName Kawabata, Ryohei
	CreatorName Hirao, Motohiro
	CreatorName Matsuyama, Jin
	CreatorName Akamaru, Yusuke
	CreatorName Morihara, Hitomi
	CreatorName Ueyama, Azumi
	NRID 1000010470197 1000010470197 researchmap permalink krkw krkw Scopus Author ID 7202562410 7202562410 CreatorName Kurokawa, Yukinori
	NRID 1000010283772 1000010283772 ORCID 0000-0001-8490-3650 0000-0001-8490-3650 researchmap permalink read0046454 read0046454 Scopus Author ID 7003914326 7003914326 CreatorName Morii, Eiichi
	NRID 1000070243459 1000070243459 CreatorName Wada, Hisashi
	NRID 1000090542118 1000090542118 researchmap permalink abcdabcdabcd abcdabcdabcd Scopus Author ID 7101627772 7101627772 CreatorName Eguchi, Hidetoshi
	NRID 1000020291445 1000020291445 researchmap permalink ydoki3251 ydoki3251 Scopus Author ID 7006390687 7006390687 CreatorName Doki, Yuichiro
Subject	Esophageal squamous cell carcinoma
	Anti-PD-1 antibody
	Biomarker
	Tumor-infiltrating T lymphocytes
	Tertiary lymphoid structure
Description	The version of record of this article, first published in Esophagus, is available online at Publisher’s website: https://doi.org/10.1007/s10388-025-01120-z.
Abstract	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.
Publisher	Springer
Source Title	Esophagus
Date of Issued	2025-04-24
Language	English
Handle URL	https://hdl.handle.net/11094/101407
PISSN	16129059
eISSN	16129067
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1007/s10388-025-01120-z
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Esophagus. 2025
DC.title	Exploring predictive biomarkers of efficacy and survival with nivolumab treatment for unresectable/recurrent esophageal squamous cell carcinoma
DC.creator	Nakai, Shigeto
	Makino, Tomoki
	Momose, Kota
	Yamashita, Kotaro
	Tanaka, Koji
	Miyata, Hiroshi
	Yamamoto, Sachiko
	Motoori, Masaaki
	Kimura, Yutaka
	Kawabata, Ryohei
	Hirao, Motohiro
	Matsuyama, Jin
	Akamaru, Yusuke
	Morihara, Hitomi
	Ueyama, Azumi
	Kurokawa, Yukinori
	Morii, Eiichi
	Wada, Hisashi
	Eguchi, Hidetoshi
	Doki, Yuichiro
DC.publisher	Springer
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-04-24
DC.identifier	https://doi.org/10.1007/s10388-025-01120-z
DC.subject	Esophageal squamous cell carcinoma
	Anti-PD-1 antibody
	Biomarker
	Tumor-infiltrating T lymphocytes
	Tertiary lymphoid structure
DC.description	The version of record of this article, first published in Esophagus, is available online at Publisher’s website: https://doi.org/10.1007/s10388-025-01120-z.
DCTERMS.abstract	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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	101407
citation_title	Exploring predictive biomarkers of efficacy and survival with nivolumab treatment for unresectable/recurrent esophageal squamous cell carcinoma
citation_author	Nakai, Shigeto
	Makino, Tomoki
	Momose, Kota
	Yamashita, Kotaro
	Tanaka, Koji
	Miyata, Hiroshi
	Yamamoto, Sachiko
	Motoori, Masaaki
	Kimura, Yutaka
	Kawabata, Ryohei
	Hirao, Motohiro
	Matsuyama, Jin
	Akamaru, Yusuke
	Morihara, Hitomi
	Ueyama, Azumi
	Kurokawa, Yukinori
	Morii, Eiichi
	Wada, Hisashi
	Eguchi, Hidetoshi
	Doki, Yuichiro
citation_publisher	Springer
citation_language	English
citation_date	2025-04-24
citation_journal_title	Esophagus
citation_doi	https://doi.org/10.1007/s10388-025-01120-z
citation_public_url	https://hdl.handle.net/11094/101407

Exploring predictive biomarkers of efficacy and survival with nivolumab treatment for unresectable/recurrent esophageal squamous cell carcinoma

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