Molecular Signature of Subtypes of Renal Cell Carcinomas and Immunotherapy Strategy

Background: Renal cell carcinoma (RCC) was not a single disease, many efforts have been devoted to identifying RCC subtypes on the basis of genomic profiling, but none has classified immunogenomic profiling based on therapeutic responses in RCC subtypes. Methods: Tumors from RCC patients from The Cancer Genome Atlas (TCGA) cohort were analyzed, and genomic profiling was performed. We classified RCC on the basis of the immunogenomic profiling of 29 immune signatures. Findings: We investigated the transcriptional changes of three RCC subtypes by RNA-seq. Gene ontology (GO) identify specific gene signatures differed significantly between KIRC, KIRP and KICH related to the distinct pathways. Site of origin within the nephron was one major determinant in the molecular and immune classification, reflecting differences between three subtypes. The Immunity High KIRC and KIRP subtype was enriched not only in immune signatures, but also including PD-L1 expression signaling, NF-kappa B signaling pathway, JAK-STAT signaling pathway and Cell cycle signaling pathway. KICH was a distinct disease that shared little genomic characteristics with KIRC and KIRP. Interpretation: The identification of RCC subtypes based on immune signatures has potential clinical implications for RCC treatment. It is imaginable that patients with higher immunity subtype of KIRC and KIRP would be more likely to respond to anti-PD-1/ PD-L1 therapy than patients with KICH subtype. CCL21 and CCL25 might be a potential target for KICH therapy. Funding Statement: This work was supported by grants from the National Natural Science Foundation (81872079, 81572538), and the Science Foundation of Tianjin (No.: 11JCZDJC19700, 16JCZDJC34400,14JCYBJC26300), 20140117, 16KG118. Declaration of Interests: None of the authors have any relevant conflicts of interest pertaining to the studies and data in this manuscript. Ethics Approval Statement: Not applicable.