Abstract
ABSTRACT
Background
Both static and longitudinal measures of circulating neutrophil-to-lymphocyte ratio (cNLR) are prognostic markers across solid malignancies, including gastroesophageal adenocarcinoma (GEA). Despite this consistency, cNLR remains poorly integrated into clinical decision-making and is generally regarded as a nonspecific inflammatory or disease-burden signal rather than a defined biological state. Analysis of a large, prospectively assembled GEA cohort showed that cNLR was only weakly associated with tumour burden or pathological response, yet both baseline and postoperative cNLR independently predicted outcome.
Methods
These observations prompted a retrospective biological investigation of what host biology cNLR captures. Using available clinically linked biospecimens, we performed multiscale analyses across complementary patient subsets encompassing peripheral-blood immune function and soluble signalling, tumour single-cell transcriptional programmes, and spatial myeloid organization within tissue.
Results
High baseline cNLR was associated with reduced circulating cytotoxic and immune-trafficking mediators, elevated angiogenesis-associated factors, neutrophil-mediated suppression of lymphocyte proliferation, impaired tumour-cell killing, and enhanced spontaneous neutrophil extracellular trap formation. Single-cell profiling identified coordinated transcriptional differences across tumour compartments, including innate, cytokine and myeloid programmes. Spatial profiling showed that myeloid abundance and organization varied across anatomical compartments; greater tumour-periphery PD-L1⁺ myeloid clustering was associated with inferior recurrence-free survival. Baseline cNLR showed little relationship with static myeloid abundance, whereas pretreatment cNLR dynamics were associated with altered cross-compartment CD8⁺– myeloid spatial relationships. Notably, higher early postoperative cNLR was associated with greater PD-L1⁺ myeloid clustering at the tumour periphery, linking the spatial architecture of the resected tumour with a systemic myeloid phenotype persisting after surgery
Conclusions
The data identify a prognostic, multilevel myeloid-associated host phenotype in GEA that is incompletely explained by tumour burden. Integrating systemic immune function, tumour single-cell transcriptomics and spatial myeloid organization demonstrates that these biological domains provide distinct, yet convergent views of the host immune phenotype captured by cNLR. These findings establish a biological framework for the clinical utility of cNLR and highlight myeloid-associated immune processes as promising targets for therapeutic intervention.
SUMMARY BOX
What is already known on this topic:
Circulating neutrophil-to-lymphocyte ratio (cNLR) is a robust prognostic marker across solid malignancies, including gastroesophageal adenocarcinoma, but is generally regarded as a nonspecific marker of inflammation or tumour burden.
What this study adds:
This study identifies elevated cNLR as a marker of a multilevel myeloid-associated host phenotype in GEA, where it captures complementary systemic and tissue-level immune features that are inadequately explained by tumour burden.
How this study might affect research, practice or policy:
These findings provide a biological framework for interpreting cNLR as an accessible indicator of systemic myeloid-associated immune state. They support prospective evaluation of cNLR as an accessible biomarker for risk stratification and treatment monitoring and highlight myeloid-associated immune processes as potential therapeutic targets.