Abstract
BACKGROUND: CCR8-expressing regulatory T cells (Tregs) are selectively localized within tumors and have gained attention as potent suppressors of anti-tumor immunity. This study focused on CCR8(+) Tregs and their interaction with CD8(+) T cells in the tumor microenvironment of human lung cancer. We evaluated their spatial distribution impact on CD8(+) T cell effector function, specifically granzyme B (GzmB) expression, and clinical outcomes. METHODS: A total of 81 patients with lung squamous cell carcinoma (LSCC) who underwent radical surgical resection without preoperative treatment were enrolled. Histological analyses were performed, utilizing an automated image analysis system for double-stained immunohistochemistry assays of CCR8/Foxp3 and GzmB/CD8. We investigated the association of CCR8(+) Tregs and GzmB(+) CD8(+) T cells in tumor tissues and further evaluated the prognostic impact of their distribution profiles. RESULTS: Histological evaluation using the region of interest (ROI) protocol showed that GzmB expression levels in CD8(+) T cells were decreased in areas with high infiltration of CCR8(+) Tregs, suggesting a suppressive effect of CCR8(+) Tregs on T cell cytotoxicity in the local tumor microenvironment. Analysis of the association with clinical outcomes showed that patients with more CCR8(+) Tregs and lower GzmB expression, represented by a low GzmB/CCR8 ratio, had worse progression-free survival. CONCLUSIONS: Our data suggest that local CCR8(+) Treg accumulation is associated with reduced CD8(+) T cell cytotoxic activity and poor prognosis in LSCC patients, highlighting the biological role and clinical significance of CCR8(+) Tregs in the tumor microenvironment. The GzmB/CCR8 ratio may be a useful prognostic factor for future clinical applications in LSCC.