Fibrinogen alpha chain is associated with response to immune checkpoint inhibitors in non-small cell lung cancer: a multi-cohort discovery and validation study.
- 1Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, P.R. China.
- 2Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, P.R. China. [email protected].
Abstract
Background
Immune checkpoint inhibitors (ICIs) have improved outcomes in non-small cell lung cancer (NSCLC), yet reliable biomarkers to predict clinical response remain limited. This study aimed to identify and validate a clinically practical biomarker reflecting neoantigen-driven immunogenicity and associated with ICI efficacy in NSCLC.Methods
We conducted a multi-phase study integrating unbiased discovery, clinical validation, and preliminary mechanistic exploration. Multi-omics profiling of a prospective NSCLC cohort (n = 28) integrated genomics, transcriptomics, and proteomics to identify fibrinogen alpha chain (FGA) as a top candidate. FGA was evaluated by quantitative immunohistochemistry in a training (n = 93) and independent validation (n = 78) cohort of patients with advanced NSCLC treated with ICIs. Multiplex immunofluorescence characterized FGA‑associated immune biology, and in vitro transcriptomic analysis explored transcriptional programs associated with FGA exposure.Results
FGA expression positively correlated with tumor neoantigen expression (r = 0.618, p < 0.001). In the training cohort, high FGA was associated with significantly prolonged progression-free survival (median PFS: 25.8 vs. 5.2 months; adjusted HR = 0.44, p = 0.003) and higher objective response rate (50.0% vs. 30.8%). These findings were confirmed in the independent validation cohort (median PFS: 38.0 vs. 14.4 months; adjusted HR = 0.42, p = 0.017). Exploratory analyses suggested elevated FGA in PD-L1-high tumors and a trend toward prolonged PFS after adjusting for PD-L1 status, though these findings require validation in larger cohorts. Multiplex immunofluorescence revealed significantly higher densities of CD4⁺, CD8⁺, and CD16a⁺ cells in FGA‑high regions (all p < 0.01). Two distinct spatial patterns were identified in both LUSC and LUAD. Pattern I featured direct immune cell infiltration into FGA-enriched regions with closer immune-tumor contact (p < 0.01), whereas Pattern II demonstrated immune concentration within FGA-outlined tumor nests with predominant accumulation on the tumor side. Transcriptomic analysis revealed that FGA exposure was associated with immune activation in both LUSC and LUAD cell lines and additional metabolic reprogramming in LUAD cell lines.Conclusions
Immunohistochemical assessment of FGA represents a clinically practical biomarker associated with improved outcomes in ICI-treated NSCLC. Preliminary mechanistic exploration suggests that FGA is associated with an immunologically active but histology-dependent tumor microenvironment.
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BibTeX
@article{liang2026fibrinogen,
title = {{Fibrinogen alpha chain is associated with response to immune checkpoint inhibitors in non-small cell lung cancer: a multi-cohort discovery and validation study.}},
author = {Hongge Liang and Yan Xu and Minjiang Chen and Jing Zhao and Wei Zhong and Mengzhao Wang},
journal = {Journal of translational medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08790-y},
url = {https://europepmc.org/article/MED/42958376},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Fibrinogen alpha chain is associated with response to immune checkpoint inhibitors in non-small cell lung cancer: a multi-cohort discovery and validation study.
AU - Hongge Liang
AU - Yan Xu
AU - Minjiang Chen
AU - Jing Zhao
AU - Wei Zhong
AU - Mengzhao Wang
PY - 2026
DA - 2026/08/14
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08790-y
UR - https://europepmc.org/article/MED/42958376
AB - Background Immune checkpoint inhibitors (ICIs) have improved outcomes in non-small cell lung cancer (NSCLC), yet reliable biomarkers to predict clinical response remain limited. This study aimed to identify and validate a clinically practical biomarker reflecting neoantigen-driven immunogenicity and associated with ICI efficacy in NSCLC.Methods We conducted a multi-phase study integrating unbiased discovery, clinical validation, and preliminary mechanistic exploration. Multi-omics profiling of a prospective NSCLC cohort (n = 28) integrated genomics, transcriptomics, and proteomics to identify fibrinogen alpha chain (FGA) as a top candidate. FGA was evaluated by quantitative immunohistochemistry in a training (n = 93) and independent validation (n = 78) cohort of patients with advanced NSCLC treated with ICIs. Multiplex immunofluorescence characterized FGA‑associated immune biology, and in vitro transcriptomic analysis explored transcriptional programs associated with FGA exposure.Results FGA expression positively correlated with tumor neoantigen expression (r = 0.618, p < 0.001). In the training cohort, high FGA was associated with significantly prolonged progression-free survival (median PFS: 25.8 vs. 5.2 months; adjusted HR = 0.44, p = 0.003) and higher objective response rate (50.0% vs. 30.8%). These findings were confirmed in the independent validation cohort (median PFS: 38.0 vs. 14.4 months; adjusted HR = 0.42, p = 0.017). Exploratory analyses suggested elevated FGA in PD-L1-high tumors and a trend toward prolonged PFS after adjusting for PD-L1 status, though these findings require validation in larger cohorts. Multiplex immunofluorescence revealed significantly higher densities of CD4⁺, CD8⁺, and CD16a⁺ cells in FGA‑high regions (all p < 0.01). Two distinct spatial patterns were identified in both LUSC and LUAD. Pattern I featured direct immune cell infiltration into FGA-enriched regions with closer immune-tumor contact (p < 0.01), whereas Pattern II demonstrated immune concentration within FGA-outlined tumor nests with predominant accumulation on the tumor side. Transcriptomic analysis revealed that FGA exposure was associated with immune activation in both LUSC and LUAD cell lines and additional metabolic reprogramming in LUAD cell lines.Conclusions Immunohistochemical assessment of FGA represents a clinically practical biomarker associated with improved outcomes in ICI-treated NSCLC. Preliminary mechanistic exploration suggests that FGA is associated with an immunologically active but histology-dependent tumor microenvironment.
SN - 1479-5876
ER -