Prognostic Immunophenotyping Clusters of Clear Cell Renal Cell Carcinoma Defined by the Unique Tumor Immune Microenvironment

Background: The tumor microenvironment affects the occurrence and development of cancers, including clear cell renal cell carcinoma (ccRCC). However, how the immune contexture interacts with the cancer phenotype remains unclear.Methods: We identified and evaluated immunophenotyping clusters in ccRCC using machine-learning algorithms. Analyses for functional enrichment, DNA variation, immune cell distribution, association with independent clinicopathological features, and predictive responses for immune checkpoint therapies were performed and validated.Results: Three immunophenotyping clusters with gradual levels of immune infiltration were identified. The intermediate and high immune infiltration clusters (Clusters B and C) were associated with a worse prognosis for ccRCC patients. Tumors in the immune-hot Clusters B and C showed pro-tumorigenic immune infiltration, and these patients showed significantly worse survival compared with patients in the immune-cold Cluster A in the training and testing cohorts (n = 422). In addition to distinct immune cell infiltrations of immunophenotyping, we detected significant differences in DNA variation among clusters, suggesting a high degree of genetic heterogeneity. Furthermore, expressions of multiple immune checkpoint molecules were significantly increased. Clusters B and C predicted favorable outcomes in 64 ccRCC patients receiving immune checkpoint therapies from the FUSCC cohort. In 360 ccRCC patients from the FUSCC validation cohort, Clusters B and C significantly predicted worse prognosis compared with Cluster A. After immunophenotyping of ccRCC was confirmed, significantly increased tertiary lymphatic structures, aggressive phenotype, elevated glycolysis and PD-L1 expression, higher abundance of CD8(+) T cells, and TCRn cell infiltration were found in the immune-hot Clusters B and C.Conclusion: This study described immunophenotyping clusters that improved the prognostic accuracy of the immune contexture in the ccRCC microenvironment. Our discovery of the novel independent prognostic indicators in ccRCC highlights the relationship between tumor phenotype and immune microenvironment.