Tumor-associated macrophage density as a predictive biomarker for survival benefit from adjuvant chemotherapy in gastric cancer

Adjuvant chemotherapy (ACT) is the standard treatment for Stage II–III gastric cancer after surgery, but biomarkers to guide patient selection are lacking. This study investigated whether spatial quantification of specific immune cell subsets could serve as such a biomarker. We performed multiplex immunofluorescence on postoperative specimens from 47 patients with Stage II–III gastric cancer. Immune cells were quantified in the tumor parenchyma and stroma. Their associations with overall survival (OS) and disease-free survival (DFS) were analyzed. High M1 macrophage density (in both the parenchyma and stroma), high parenchymal CD56dim natural killer (NK)-cell density, and high stromal M2 macrophage density were significantly associated with better OS and DFS in patients receiving ACT. Importantly, only patients with high M2 macrophage density derived a significant OS benefit from ACT compared with observation alone, in either the parenchyma or stroma (e.g., parenchyma: hazard ratio [HR] = 0.28, 95% confidence interval [CI]: 0.08–0.96, p = 0.029; stroma: HR = 0.14, 95% CI: 0.03–0.66, p = 0.003). A significant DFS benefit from ACT was also observed in patients with high stromal M2 density (HR = 0.22, 95% CI: 0.06–0.86, p = 0.016). No other immune cell subset consistently predicted the benefit of ACT. In conclusion, the pre-existing density and spatial distribution of tumor-associated macrophages are key determinants of prognosis and ACT's efficacy in gastric cancer.