CD8(+) T Cell-Based Molecular Classification With Heterogeneous Immunogenomic Landscapes and Clinical Significance of Clear Cell Renal Cell Carcinoma

The tumor microenvironment (TME) exerts a high impact on tumor biology and immunotherapy. The heterogeneous phenotypes and the clinical significance of CD8(+) T cells in TME have not been fully elucidated. Here, a comprehensive immunogenomic analysis based on multi-omics data was performed to investigate the clinical significance and tumor heterogeneity between CD8(+) T cell-related molecular clusters. We identified two distinct molecular clusters of ccRCC (C1 and C2) in TCGA and validated in E-MTAB-1980 cohorts. The C1 cluster was characterized by unfavorable prognosis, increased expression levels of CD8(+) T cell exhaustion markers, high immune infiltration levels as well as more immune escape mechanisms. The C2 cluster was featured by favorable prognosis, elevated expression levels of CD8(+) T cell effector markers, low load of copy number loss and low frequency of 9p21.3 deletion. Moreover, the effect of molecular classifications on Nivolumab therapeutic efficacy in the CheckMate 025 cohort was examined, and the C2 cluster exhibited a better prognosis. Taken together, we determine two CD8(+) T cell-related molecular clusters in ccRCC, and provide new insights for evaluating the functions of CD8(+) T cells. Our molecular classification is a potential strategy for prognostic prediction and immunotherapeutic guidance for ccRCC patients.