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Elevation of the Prognostic Factor Plasma Fibrinogen Reflects the Immunosuppressive Tumor Microenvironment in Esophageal Squamous Cell Carcinoma

  • Thoracic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Introduction

Despite previous reports on the clinical significance of plasma fibrinogen (FNG) levels as a prognostic indicator of ESCC, its underlying mechanism remains unclear. This study aimed to validate the prognostic impact of plasma FNG levels and clarify its relationship with primary tumors in patients with esophageal squamous cell carcinoma (ESCC).

Methods

The prognostic impact of FNG was evaluated in patients with ESCC who underwent esophagectomy between 2000 and 2019. The RNA sequencing of the primary ESCC site, which was from pre-operative biopsy, was performed, followed by immune profile characterization using an immunogram. Those profiles were assessed via the immunohistochemical staining of tumor-associated macrophages (TAMs) and clinical response to nivolumab.

Results

Multivariate analysis identified FNG as a significant prognostic factor in ESCC. The immunogram suggested an immunosuppressive tumor environment in the high-FNG group. Immunostaining with the TAM markers CD163 and CD204, revealed that the high-FNG group had significantly higher number of TAMs compared with the low-FNG group. The immunosuppressive characteristics were clinically validated in patients with metastatic ESCC; those who had elevated FNG levels showed poor response to nivolumab.

Conclusion

This study successfully validated the prognostic impact of plasma FNG levels in an expanded cohort with ESCC. Accordingly, our findings showed that increased plasma FNG reflects an immunosuppressive tumor microenvironment that facilitates tumor progression and poor responses to nivolumab.

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Acknowledgment

We wish to thank Michiru Sugimoto, a laboratory staff member at the Department of Surgery in Keio University School of Medicine, and Kumiko Motooka, a staff member at the Department of Surgery in Keio University School of Medicine, for their help with the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Surgery, Keio University School of Medicine, Tokyo, Japan

    Shota Hoshino MD, Satoru Matsuda MD, PhD, Hirofumi Kawakubo MD, PhD, Shigeo Yamaguchi MD, Ph.D, Kazuaki Matsui MD, Tomoyuki Irino MD, PhD, Kazumasa Fukuda PhD, Rieko Nakamura MD, PhD & Yuko Kitagawa MD, PhD

  2. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan

    Kohei Nakamura MD, PhD, Eriko Aimono MD, PhD & Hiroshi Nishihara MD, PhD

  3. Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan

    Hajime Okita M.D., Ph.D

  4. Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan

    Hiroya Takeuchi MD, PhD

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  1. Shota Hoshino MD
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Corresponding author

Correspondence to Satoru Matsuda MD, PhD.

Ethics declarations

Author Y.K received lecture fees from CHUGAI PHARMACEUTICAL CO., LTD., TAIHO PHARMACEUTICAL CO., LTD, ASAHI KASEI PHARMA CORPORATION, Otsuka Pharmaceutical Factory Inc., SHIONOGI & CO., LTD., Nippon Covidien Inc., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K. Author Y.K was supported by grants from CHUGAI PHARMACEUTICAL CO., LTD., TAIHO PHARMACEUTICAL CO., LTD, Yakult Honsha Co. Ltd., AsahiKASEI Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., ONO PHARMACEUTICAL CO., LTD., TSUMURA & CO., Kyouwa Hakkou Kirin Co., Ltd., DAINIPPON SUMITOMO PHARMA Co., Ltd., EA Pharma Co., Ltd., Astellas Pharma Inc., Toyama Chemical Co., Ltd., MEDICON INC., KAKEN PHARMACEUTICAL CO. LTD., Eisai Co., Ltd., Otsuka Pharmaceutical Factory Inc., TEIJIN PHARMA LIMITED., NIHON PHARMACEUTICAL CO., LTD., and Nippon Covidien Inc. Author Y.K held an endowed chair provided by CHUGAI PHARMACEUTICAL CO., LTD. and TAIHO PHARMACEUTICAL CO., LTD, outside the submitted work.

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PleSSision-160 gene list (TIF 595 kb)

10434_2022_11974_MOESM3_ESM.tif

MA plot of gene expression changes. The log2 fold change for a particular comparison is plotted on the y-axis, whereas the average of the counts normalized by size factor is shown on the x-axis. Each gene is represented by a dot. Genes with an adjusted p value below a threshold (here 0.1 as the default) are shown in red (TIF 112 kb)

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Hoshino, S., Matsuda, S., Kawakubo, H. et al. Elevation of the Prognostic Factor Plasma Fibrinogen Reflects the Immunosuppressive Tumor Microenvironment in Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 29, 6894–6904 (2022). https://doi.org/10.1245/s10434-022-11974-7

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  • DOI: https://doi.org/10.1245/s10434-022-11974-7

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