Abstract
Purpose: In the tumor microenvironment, the functional differences among various tumor-associated macrophages (TAM) are not completely clear. Tumor-associated macrophages are thought to promote the progression of cancer. This article focuses on exploring M2 macrophage-related factors and behaviors of renal clear cell carcinoma.Method: We obtained renal clear cell carcinoma data from TCGA-KIRC-FPKM, GSE8050, GSE12606, GSE14762, and GSE3689. We used the “Cibersort” algorithm to calculate type M2 macrophage proportions among 22 types of immune cells. M2 macrophage-related co-expression module genes were selected using weighted gene co-expression network analysis (WGCNA). A renal clear cell carcinoma prognosis risk score was built based on M2 macrophage-related factors. The ROC curve and Kaplan–Meier analysis were performed to evacuate the risk score in various subgroups. The Pearson test was used to calculate correlations among M2 macrophage-related genes, clinical phenotype, immune phenotype, and tumor mutation burden (TMB). We measured differences in co-expression of genes at the protein level in clear renal cell carcinoma tissues.Results: There were six M2 macrophage co-expressed genes (F13A1, FUCA1, SDCBP, VSIG4, HLA-E, TAP2) related to infiltration of M2 macrophages; these were enriched in neutrophil activation and involved in immune responses, antigen processing, and presentation of exogenous peptide antigen via MHC class I. M2-related factor frequencies were robust biomarkers for predicting the renal clear cell carcinoma patient clinical phenotype and immune microenvironment. The Cox regression model, built based on M2 macrophage-related factors, showed a close prognostic correlation (AUC = 0.78). The M2 macrophage-related prognosis model also performed well in various subgroups. Using western blotting, we found that VSIG4 protein expression levels were higher in clear renal cell carcinoma tissues than in normal tissues.Conclusion: These co-expressed genes were most related to the M2 macrophage phenotype. They correlated with the immune microenvironment and predicted outcomes of renal clear cell carcinoma. These co-expressed genes and the biological processes associated with them might provide the basis for new strategies to intervene via chemotaxis of M2 macrophages.
Highlights
Renal clear cell carcinoma (RCC) accounts for 80–90% of all renal cell carcinomas; clear cell carcinoma is not sensitive to chemotherapy and radiotherapy (Hsieh et al, 2017)
We calculated macrophage M2 cell proportions based on the LM22 matrix using the CIBERSORT (Chen et al, 2018) algorithm, Cibersort was used as an obvious method to evaluate the significance of infiltration of immune cells in the samples
We identified the biological processes associated with M2-type macrophage proportion
Summary
Renal clear cell carcinoma (RCC) accounts for 80–90% of all renal cell carcinomas; clear cell carcinoma is not sensitive to chemotherapy and radiotherapy (Hsieh et al, 2017) For this reason, radical surgery has become the main treatment method. Immune regulation plays a crucial role in the renal clear cell carcinoma microenvironment This process includes immune checkpoints [mainly programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)], as well as regulatory T cells, the original source of suppressor cell tumor-associated macrophages, and type 2 innate and adaptive lymphocytes (Xu W. et al, 2020). As tumors progress, increasing numbers of M2 macrophages appear, resulting in a weaker antigen presentation effect. For this reason, targeting macrophages has become a new therapeutic strategy (DeNardo and Ruffell, 2019).
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