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 PDL1 positive 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 spatial relationships between CD8 positive cells and myeloid cells. Notably, higher early postoperative cNLR was associated with greater PDL1 positive 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.
Dhoparee-Doomah, I., Li, Y., Al Dow, M., Hajhashemi, S., Brassard, A., Benizri, N., Leo, S., Milne, K., Xu, M. Z., Qiu, Q., Nelson, B. H., Fiset, P.-O., Giannias, B., Bourdeau, F., Spicer, J., Ferri, L. E., Tchervenkov, J., Ma, K., Cools-Lartigue, J.
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