Spatial immune cell architecture after gastric cancer surgery predicts prognosis

Gastric cancer remains a major global health burden with high mortality due to late-stage diagnosis and limited treatment efficacy. Emerging evidence demonstrates that the tumor microenvironment, particularly immune cell infiltration patterns and hypoxia-induced immunosuppression, plays a critical role in cancer progression. This study investigates the spatial immune cell architecture in postoperative gastric cancer tissues to identify prognostic biomarkers and guide personalized immunotherapy strategies.

To investigate the spatial distribution pattern, density, and proportional features of important immune cells in the tumor microenvironment following radical gastrectomy for gastric cancer, assess their relationships with patients' 5-year overall survival (OS) and recurrence-free survival following surgery, and provide an immunological foundation for prognostic assessment.

A total of 112 patients with stage I-III gastric cancer who underwent R0 resection between June 2018 and June 2020 were included retrospectively. Paraffin-embedded specimens of postoperative cancer tissues and adjacent tissues were collected. The multicolor immunohistochemistry technique was used, and pan-cytokeratin staining was performed synchronously with 4,6-diamidino-2-phenylindole nuclear staining. The sections were scanned by the Vectra Polaris™ full-spectrum imaging system, and cell phenotype identification and spatial localization analysis were performed via InForm^® 2.6 software. The independent prognostic value of OS/disease-free survival and immunological markers was assessed (tumor-node-metastasis stage, Lauren classification), and the Kaplan-Meier survival curve was used to analyze the survival differences between the high/low immune infiltration groups (log-rank test).

The density of CD8+ T cells in the invasion margin area (median: 248.5/mm²) was significantly greater than that in the tumor core area (108.3/mm², P < 0.001). The 5-year OS rate was high in patients with a high CD8+ density (> 220/mm²; 68.2%), low-density group: 42.1%, P = 0.003. An independent correlation between extended disease-free survival and a CD8+/forkhead box protein 3+ (FoxP3+) ratio > 2.5 was found [hazard ratio (HR) = 0.47, 95% confidence interval (CI): 0.29-0.76]. The risk of death was greater for those with a fraction of programmed death ligand 1+ tumor cells > 10% (HR = 2.15, 95%CI: 1.32-3.51). The enrichment of CD68+CD163+ M2 macrophages in the core area of the tumor predicted an increased risk of recurrence (HR = 1.72, P = 0.018). An immune prognosis scoring system was constructed on the basis of least absolute shrinkage and selection operator (regression, integrating the density of the CD8+ marginal zone, the CD8+/FoxP3+ ratio, and the 5-year OS prediction area under the curve was 0.81 (95%CI: 0.74-0.88).

The spatial distribution pattern of immune cells in the tumor microenvironment following gastric cancer surgery and the percentages of particular subgroups (programmed death ligand 1+ and CD8+/FoxP3+ tumor cells) are independent predictors of long-term survival.