Exploration of the relationships between tumor mutation burden with immune infiltrates in clear cell renal cell carcinoma

Abstract

Background: Whether tumor mutation burden (TMB) correlated with improved survival outcomes or promotion of immunotherapies remained controversy in various malignancies. We aimed to investigate the prognosis of TMB and the potential association with immune infiltrates in clear cell renal cell carcinoma (ccRCC). Methods:We downloaded the somatic mutation data of 336 ccRCC patients from the Cancer Genome Atlas (TCGA) database, and analyzed the mutation profiles with "maftools" package. TMB was calculated and we classified the samples into high-TMB and low-TMB group. Differential analysis was conducted to compare the expression profiles between two groups using "limma" package, and we identified the 9 hub TMB-related signature from batch survival analysis. Gene ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) were performed to screen significantly enriched pathways between two groups. Based on the TIMER database, we further assessed the relationships of the mutants of 9 TMB-related signature with immune infiltration levels in ccRCC. Besides, we utilized the "CIBERSORT" package to estimate the abundance of 22 immune fractions between low-and high-TMB groups, and the significant difference were determined by Wilcoxon rank-sum test. Furthermore, Cox regression model combined with survival analysis were used to evaluate the prognostic value of immune cells. Last, we constructed a Tumor Mutation Burden Prognostic Index (TMBPI) from multivariate Cox results and Receiver Operating Characteristic (ROC) curve was drawn to assess the predictive accuracy.Results: Single nucleotide polymorphism (SNP) occurred more frequently than insertion or deletion, and C>T was the most common of SNV in ccRCC. Higher TMB levels conferred poor survival outcomes, associated with higher tumor grades and advanced pathological stages. A total of 1,265 differentially expressed genes were obtained and top 19 immune-related genes were identified in Venn diagram. GSEA revealed that patients in higher TMB groups correlated with MAPK signaling pathway, Wnt signaling pathway and pathway in cancers. Moreover, we identified 9 hub TMB-related immune genes related with survival and mutants of 9 signature were associated with lower immune infiltrates. In addition, infiltration levels of CD8+ T cell, CD4+ memory resting T cell, M1 and M2 macrophages, as well as dendritic resting cells in high-TMB group were lower than that in low-TMB group, especially the level of CD8+ T cell and macrophage correlated negatively with prognosis of ccRCC. Last, the TMBPI was constructed and the AUC of ROC curve was 0.666.Conclusions: Higher TMB correlated with poor survival outcomes and might inhibit the immune infiltrates in ccRCC. The mutants of 9 hub TMB-related immune signature conferred lower immune cells infiltration which deserved further validation.

CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC)

“…Previous studies have demonstrated that TILs within the TME can be regarded as a prognostic indicator in ccRCC (21). Besides, the results of GO and KEGG promoted us to continue to investigate the role of CTLA4 in TILs in ltration, which affected the ICBs' response.…”

Biological Omics Analysis of Tumor Mutation Burden Combined with Immune Infiltrates in Uterine Corpus Endometrial Carcinoma

“…Lv et al (2020) revealed that the prognosis of bladder cancer patients with higher TMB was better so that TMB was considered to be a powerful predictor of tumor behavior and response to immunotherapy (38). However, in some types of cancer, such as clear cell renal cell carcinoma, patients with high TMB levels showed worse survival outcomes (24).…”

“…In contrast, there was growing evidence that higher TMB in renal cell carcinoma (RCC) was correlated with immune cell exclusion and the immunologically cold phenotypes. Accordingly, higher TMB was supposed to be associated with worse survival in RCC (24,25). These ndings stated that TMB levels may have contradictory predictions in different tumor types.…”

Construction of a Prognostic Value Model in Papillary Renal Cell Carcinoma by Immune-Related Genes

“…pro les and have constructed prognostic multigene signatures that can divide patients into different risk groups [15][16][17]. Previous studies have shown that IRGs were associated with the immune response intensity and predicted the prognosis of patients with PRCC [18,19].…”