Abstract
PURPOSE: Tumor microenvironment is important in the progression of clear cell renal cell carcinoma (ccRCC), and its prognostic value is still unclear. Recent reports demonstrated tumor-infiltrating CD39(+)CD8(+) T cells are abundant, but their function remains obscure. We aim to assess clinical value of CD39(+)CD8(+) T cells and seek a potential therapeutic target in ccRCC. EXPERIMENTAL DESIGN: We immunohistochemically evaluated clinical value of CD39(+)CD8(+) T cells in a retrospective Zhongshan Hospital cohort of 243 ccRCC patients. Fresh tumor samples (n = 48), non-tumor tissues and peripheral blood for flow cytometry analyses were collected to analyze immune cell functions from Zhongshan Hospital. The survival benefit of tyrosine kinase inhibitors (TKIs) in this subpopulation was evaluated. Kaplan-Meier analysis and COX regression model were applied for survival analyses. Bioinformatics analysis performed in TCGA KIRC cohort and the scRNA-seq cohort. RESULTS: We found that accumulation of CD39(+)CD8(+) T cells indicated poor prognosis (p < 0.0001) and indicated therapeutic benefit of TKIs therapy (p = 0.015). CD39(+)CD8(+) T cells showed decreased TNF-α and IFN-γ with elevated PD-1 and TIM-3 expression. Further analysis of tumor-infiltrating immune cell landscape in the ccRCC revealed the positive correlation between CD39(+)CD8(+) T cells and Tregs (p = 0.037) and M2-polarized macrophages (p < 0.0001). Finally, inhibition of CD39 partially restores the anti-tumor function of CD8(+) T cells. CONCLUSIONS: High CD39(+)CD8(+) T cells indicated poor prognosis in ccRCC, due to impaired anti-tumor function of CD39(+)CD8(+) T cells and indicated therapeutic benefit of TKIs therapy.