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.