Abstract
BackgroundRecent research of clear cell renal cell carcinoma (ccRCC) is focused on the tumor immune microenvironment (TIME). Chromatin accessibility is critical for regulation of gene expression. However, its role in different immunological subtypes of ccRCC based on immune cell infiltration has not been systematically studied.MethodsFive hundred thirty patient data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) were adopted to estimate immune cell infiltration. Twenty-four types of immune cells were evaluated with single-sample Gene Set Enrichment Analysis (ssGSEA). Patients were divided into two clusters based on immune cell infiltration. Systematic chromatin accessibility analysis was conducted based on the two clusters.ResultsWe compared the relative expression of the immune gene signatures among 530 patients of TCGA-KIRC using ssGSEA. Overall survival (OS) analysis revealed 10 types of immune cells were significantly associated with prognosis. Patients were divided into two clusters based on 24 types of immune cell infiltration. Immune cell signals as well as PD-1/PD-L1 signal were higher in cluster 1. Among the two clusters, 2,400 differential peaks were found in TCGA-KIRC Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) data. The distribution of differential peaks and prognosis-related immune cells in 23 chromosomes are essentially the same. There is no peak distribution downstream. The proportion of peaks upstream of the 5’ transcription start site decreases, and both sides of binding regions of the TSS 0.1-1 kb becomes smaller. Enrichment analysis of GO and KEGG of these differential peaks showed that they are remarkably related to the immune regulation in tumor microenvironment. Known motifs and de novo motifs were found by linking motif annotations to different peaks. Survival analysis of related motif transcription factors were prognostic. The GSEA enrichment analysis showed that high SP1 expression positively correlates with TGF-beta signaling and inflammatory response, while negatively correlates with TNF-alpha signaling via NFKB. High KLF12 expression negatively correlates with interferon gamma response, IL2-STAT5 signaling, TNF-alpha signaling via NFKB, IL6-JAK-STAT3 signaling.ConclusionThe abnormality of chromatin accessibility may play an important regulatory role in ccRCC immunity.
Highlights
Renal cell carcinoma (RCC) is one of the most common malignant tumors in the urinary system
Overall survival analysis of every type of immune cells was performed (Figure 1, Supplementary Table 2), and we found that the presence of Treg, aDC, natural killer (NK) CD58 bright cells, and Th2 cells was associated with unfavorable prognosis (p < 0.001, p = 0.013, p < 0.001, and p = 0.00019), while T helper (Th) 17 cells, neutrophils, mast cells, NK cells, Tgd, and Tcm were associated with favorable prognosis (p < 0.015, p = 0.00055, p < 0.0036, p = 0.0084, p = 0.04, and p = 0.0028) in clear cell renal cell carcinoma (ccRCC)
The immune cell interaction network displays a comprehensive landscape of cell cluster and their effects on the OS of patients with ccRCC, which is divided into four categories according to the K-means clustering algorithm (Figure 2B)
Summary
Renal cell carcinoma (RCC) is one of the most common malignant tumors in the urinary system. The main pathological type is clear cell renal cell carcinoma (ccRCC), one of the most aggressive type [3], accounting for approximately 75% of all RCCs [4]. With the breakthrough of immunotherapy, the tumor immune microenvironment has increasingly attracted more attention in cancer research. RCC is a tumor with one of the most immune cell infiltration in pan-cancer [3], and the tumor immune microenvironment has become the focus for research in ccRCC [4, 5]. Recent research of clear cell renal cell carcinoma (ccRCC) is focused on the tumor immune microenvironment (TIME). Its role in different immunological subtypes of ccRCC based on immune cell infiltration has not been systematically studied
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