Tumor-infiltrating TNFRSF9(+) CD8(+) T cells define different subsets of clear cell renal cell carcinoma with prognosis and immunotherapeutic response

OBJECTIVES: Tumor necrosis receptor super family (TNFRSF) plays an important role in regulating the function of CD8(+) T cells. In this study, we explored the clinical significance and immune profile of TNFRSF9(+) CD8(+) T cells in clear cell renal cell carcinoma (ccRCC) METHODS: The infiltration of immune cells was determined by immunohistochemistry in ZS cohort from our hospital and their prognostic value was further determined by Cox regression. Functional status of CD8(+) T cells in ccRCC was determined by flow cytometry in 29 fresh tumor samples. In silico analysis on a TCGA cohort and other datasets was performed to further demonstrate our findings. RESULTS: High TNFRSF9(+) CD8(+) T cells infiltration was associated with inferior overall survival in ZS cohort (p = .0016) and TCGA-KIRC cohort (p = .018). TNFRSF9(+) CD8(+) T cells expressed higher exhaustion markers (PD-1, TIM-3, CTLA-4, and TIGIT), and effector markers (IFN-γ, GZMB, CD107a, and Ki-67), than their TNFRSF9 negative counterparts. In silico analysis indicated the expression of TNFRSF9 was significantly correlated with IFNG, GZMK, MKI-67, PDCD1, HAVCR2, TIGIT, and CTLA-4 in CD8(+) T cells. However, higher TNFRSF9 signature was correlated with larger tumor size shrinkage (p = .003) and better progression-free survival (p = .012) in patients treated with nivolumab but not everolimus. CONCLUSION: TNFRSF9(+) CD8(+) T cells, which possessed both exhaustion and effector phenotype, were identified as an adverse prognosticator in ccRCC. These cells enrichment was associated with better immunotherapy response which indicated these cells potentially be crucial in immunotherapy.