A Novel Lymphangiogenesis-Related Gene Signature can Predict Prognosis and Immunosuppressive Microenvironment in Patients with Clear Cell Renal Cell Carcinoma

Abstract

Background: Lymphangiogenesis represents a key event in the progression and metastasis of patients with clear cell renal cell carcinoma (ccRCC). Nevertheless, the prognostic value of lymphangiogenesis-related genes (LRGs) in ccRCC patients remains unknown. Method: Differential analyses were performed to identify differentially expressed LRGs between normal and tumor tissues. A univariate Cox analysis was performed to identify differently expressed LRGs associated with overall survival (OS). LASSO and multivariate Cox analyses were performed to construct and optimize the LRG signature. To further explore the molecular characterization of the LRG signature, a functional enrichment analysis, immune signature, somatic mutations, and drug sensitivity were assessed. Immunohistochemistry (IHC) and immunofluorescence staining were performed to validate the relationship between lymphangiogenesis and immunity using our ccRCC samples. Results: Four candidate genes (IL4, CSF2, PROX1, and TEK) were eventually available to construct the LRG signature in the training set. Patients in the high-risk group had a shorter survival than those in the low-risk group. The LRG signature was an independent prognostic factor of OS. These results were confirmed in the validation group. The LRG signature was correlated with immunosuppressive cell infiltration, T cell exhaustion markers, somatic mutations, and drug sensitivity. The IHC and immunofluorescence staining results confirmed the correlation between lymphangiogenesis and CD163 + macrophages, exhausted CD8 + PD-1 + , and CD8 + LAG3 + T cells. Conclusion: A novel prognostic signature based on LRGs could provide insight into the prognostic evaluation and treatment of ccRCC patients.

A novel risk signature based on liquid-liquid phase separation-related genes reveals prognostic and tumour microenvironmental features in clear cell renal cell carcinoma

“…It has been shown that conventional TNM staging may be inaccurate in predicting the prognosis of ccRCC patients because it does not take into account the effect of gene expression on prognosis [29]. Many studies are currently trying to predict the prognosis of patients with ccRCC by establishing risk signatures based on the results of gene sequencing and combining them with clinical information [30][31][32]. But the overall efficiency of clinical translation is low.…”

PD1/PD-L1 blockade in clear cell renal cell carcinoma: mechanistic insights, clinical efficacy, and future perspectives

“… [ 28 ] Lymphangiogenesis prediction model IL4, CSF2, PROX1 and TEK PD1 expression was higher in high-risk group Providing new ideas for the prognosis evaluation and treatment of ccRCC patients. [ 29 ] Prognostic model IRF6, TEK, PLCB2, ABCB1, TGFA, COL4A5, PLOD2 and TUBB6 Elevated expression of high-risk groups of PD1. To predict the clinical prognosis and the efficacy of immunotherapy in ccRCC patients.…”

Identification of a novel lymphangiogenesis signature associated with immune cell infiltration in colorectal cancer based on bioinformatics analysis

“…Lymph Node Metastasis Associated Transcript 1 (LNMAT1) promotes lymphatic metastasis and acts as a potential therapeutic target for LN-metastatic bladder cancer therapy [ 26 ]. Vascular endothelial growth factor C (VEGF-C), interleukin-4 (IL-4), colony-stimulating factor 2 (CSF2), prospero homeobox 1 (PROX1), and TEK receptor Tyrosine Kinase (TEK) is significantly associated with lymph node metastasis in renal cell carcinoma (RCC) [ 27 , 28 ]. Collagen and calcium-binding EGF domain-1 (CCBE1) and neuropilin-2 (NRP2) promote lymphangiogenesis and lymphatic metastasis in CRC and can be used as therapeutic targets in CRC [ 29 – 31 ].…”