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Background <p>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> Methods <p>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> Results <p>In surgical specimens, clinical response (vs. non-response) to nivolumab correlated significantly with CD8<sup>+</sup> lymphocyte count (160 vs<i>.</i> 95.2 cells/field, <i>P</i> = 0.0494), CD8/Foxp3 ratio (6.52 vs<i>.</i> 2.72, <i>P</i> = 0.0053), and TLS density (0.21/mm<sup>2</sup> vs. 0.10/mm<sup>2</sup>, <i>P</i> = 0.0005). In terms of overall survival, multivariate analysis identified CD8/Foxp3 ratio (hazard ratio [HR] = 1.83, <i>P</i> = 0.0050) and TLS density (HR = 1.67, <i>P</i> = 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<i>.</i> 124 cells/mm<sup>2</sup>, <i>P</i> = 0.0344), CCR8<sup>+</sup> lymphocyte count (62.6 cells/mm<sup>2</sup> vs<i>.</i> 140 cells/mm<sup>2</sup>, <i>P</i> = 0.0355), CD8/Foxp3 ratio (2.09 vs<i>.</i> 0.89, <i>P</i> = 0.040), and CD8/CCR8 ratio (2.34 vs<i>.</i> 0.89, <i>P</i> = 0.0020). Multivariate analysis also identified CD8/CCR8 ratio in endoscopic biopsies (HR = 1.66, <i>P</i> = 0.0313) as an independent prognostic parameter.</p> Conclusions <p>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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月24日

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  • 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

摘要

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.