TERT promoter methylation predicts overall survival, immune cell infiltration and response to immunotherapy in clear cell renal cell carcinoma.

Abstract

Purpose: Telomerase reverse transcriptase (TERT) is one of the most well-established oncogenes in tumor development and progression. It is widely known that TERT promoter hypermethylation is associated with its transcription activation. Despite its canonical role in maintaining telomere length in cancer cells, TERT is also involved in various oncogenic processes independent of its enzymatic activity. However, the role of TERT in the tumor immune microenvironment has been largely unexplored. Hence, we assessed the associations between TERT promoter methylation and its expression, clinicopathological features, overall survival, immune cell infiltration, and response to immune checkpoint inhibitor therapy in clear cell renal cell carcinoma.

Methods: A single-sample gene-set enrichment analysis algorithm was used to quantify the relative abundance of each type of immune cell infiltration in the tumor microenvironment (TME) of the TCGA KIRC cohort. We used Spearman's rank correlation to calculate the correlation coefficients between TERT promoter methylation and immune cell infiltration. The relative methylation of cg11625005 in our validation cohort was detected by pyrosequencing and the relative infiltration of CD4 + and CD8 + T cells infiltration in the TME was measured by immunohistochemistry.

Results: The TERT promoter was significantly hypermethylated in clear cell renal cell tumor tissues, which was related to the transcriptional activation of TERT. TERT promoter hypermethylation was significantly correlated with aggressive phenotypes and poor survival in clear cell renal cell carcinoma patients. Furthermore, TERT promoter methylation was significantly positively correlated with CD4 + /CD8 + T cells infiltration and immune checkpoint molecule (CTLA-4, TIGIT, PD-1 and LAG3) expression. And TERT promoter methylation was correlated with the therapeutic response to anti-PD1 immunotherapy.

Conclusion: TERT promoter methylation is a promising predictive biomarker of immune cell infiltration, overall survival, clinicopathological characteristics and response to anti-PD1 immunotherapy treatment in clear cell renal cell carcinoma patients.