# Plasma Fibrinogen Predicts Response to Immune Checkpoint Inhibitor by Inflammatory Tumor Microenvironment in Esophageal Cancer

## TL;DR

High plasma fibrinogen levels in esophageal cancer patients predict poor response to immune therapy and are linked to increased tumor inflammation.

## Contribution

This study identifies plasma fibrinogen as a novel biomarker for immune checkpoint inhibitor response in esophageal cancer.

## Key findings

- Elevated plasma fibrinogen correlates with lower ICI response rates and worse survival in ESCC patients.
- High fibrinogen tumors show increased tumor-associated neutrophil infiltration, independent of PD-L1 expression.
- Chemo-ICI therapy is more effective in high-fibrinogen patients compared to dual-ICI therapy.

## Abstract

Plasma fibrinogen (FNG) is a prognostic marker in esophageal squamous cell carcinoma (ESCC). However, its predictive value for immune checkpoint inhibitor (ICI) efficacy and the underlying mechanisms remain unclear. This study aimed to evaluate the clinical significance of plasma FNG levels in ICI‐treated ESCC patients and investigate its association with tumor‐associated neutrophils (TANs) and genomic alterations.

A retrospective, multicenter analysis of 167 ESCC patients treated with ICIs was performed. TANs were quantified via immunohistochemistry using CD11b and CD66b staining, and PD‐L1 expression was assessed using the tumor proportion score (TPS). Whole‐exome and RNA sequencing were conducted to analyze genomic and transcriptomic profiles.

Elevated plasma FNG levels correlated with lower ICI response rates and decreased survival. In first‐line treatment, chemo‐ICI therapy demonstrated superior efficacy compared to dual‐ICI therapy in high‐FNG patients, while the reverse trend was observed in low‐FNG patients. High‐FNG tumors showed increased TAN infiltration, independent of PD‐L1 expression. RNA sequencing revealed enrichment of neutrophil activation and extravasation pathways in high‐FNG tumors.

Elevated plasma FNG levels predict poor prognosis and reduced ICI efficacy in ESCC. They may be potential biomarkers for first‐line ICI‐based therapy and correlate with TAN infiltration. Further validation and mechanistic investigations are warranted.