High intratumoral heterogeneity in clear cell renal cell carcinoma is associated with reduced immune response and survival.

Background: Clear cell renal cell carcinoma (ccRCC) exhibits high intratumor heterogeneity (ITH), which drives progression, metastasis, and treatment resistance. Nevertheless, clinically applicable tools for predicting patient prognosis based on ITH remain unavailable, and the association between ITH and immune cell response is a matter of debate. The objective of this study was to establish ITH as a clinically relevant biomarker capable of predicting outcomes and informing treatment strategies in ccRCC.

Methods: The Bioconductor R package Maftools was used to analyze somatic variants of ccRCC from The Cancer Genome Atlas (TCGA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to estimate immune cell compositions. A mutant-allele tumor heterogeneity (MATH) algorithm was used to measure ITH, and we explored its correlation with clinical parameters and immune cell response.

Results: Our analysis revealed that lower MATH values were significantly associated with increased infiltration of activated dendritic cells (P=0.048) and reduced levels of immunosuppressive regulatory T cells (Tregs; P=0.02), suggesting enhanced antitumor immunity in less heterogeneous tumors. Conversely, high MATH values correlated with worse overall survival and a suppressed immune microenvironment. These findings support the potential of MATH as a stratification biomarker for ccRCC patients, helping identify those who may benefit from immunotherapy or targeted therapies.

Conclusions: High MATH value correlates with worse survival and decreased immune response in ccRCC patients.