The immunosuppressive role of CCR8⁺ Tregs in gastric cancer

Background: Gastric cancer remains one of the most common causes of cancer death, with a notably high incidence in East Asian countries. Regulatory T cells (Tregs) suppress antitumor immunity in the tumor microenvironment, and recent studies have identified C-C motif chemokine receptor 8 (CCR8) as a selective marker for tumor-infiltrating activated Tregs. However, the role of CCR8⁺ Tregs in gastric cancer remains unclear. Methods: This study retrospectively analyzed 80 gastric cancer patients who underwent curative resection. Immunohistochemistry dual staining for CCR8/Foxp3 and granzyme B/CD8 was performed, followed by automated image analysis and spatial profiling. The correlation between CCR8⁺ Tregs and CD8⁺ T cells, as well as their prognostic significance, was evaluated. Results: CCR8⁺ Treg density positively correlated with CD8⁺ T cell infiltration. However, a low CD8⁺ T cell/CCR8⁺ Treg ratio was significantly associated with worse recurrence-free survival (P = 0.023). Reduced granzyme B expression was observed in CCR8⁺ Treg-dense hotspots, suggesting the presence of a localized immunosuppressive environment. Spatial analysis revealed that CCR8⁺ Tregs were preferentially localized at the tumor invasion front. Furthermore, distance analysis showed that fewer CD8⁺ T cells were present around CCR8⁺ Tregs than around CCR8⁻ Tregs, suggesting a localized immunosuppressive effect that may restrict CD8⁺ T cell proliferation. Conclusions: Our findings suggest that CCR8⁺ Tregs suppress antitumor immunity in gastric cancer by affecting surrounding CD8⁺ T cells through spatial segregation. Targeting CCR8⁺ Tregs may offer a promising strategy to improve the efficacy of immunotherapy in gastric cancer.