CXCL12 and CD3E as Indicators for Tumor Microenvironment Modulation in Bladder Cancer and Their Correlations With Immune Infiltration and Molecular Subtypes

Abstract

Bladder cancer (BLCA) represents the ninth most common malignant tumor in the world and is characterized by high recurrence risk. Tumor microenvironment (TME) plays an important role in regulating the progression of BLCA. Immunotherapy, including Bacillus Calmette-Guerin (BCG) and programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), is closely associated with TME and is widely used for treating BLCA. But parts of BLCA patients have no response to these treatment ways, thus a better understanding of the complex TME of BLCA is still needed. We downloaded the gene expression profile and corresponding clinical information of 414 BLCA patients from the TCGA database. Via the ESTIMATE and CIBERSORT algorithm, we identified the two hub genes (CXCL12 and CD3E) and explored their correlations with immune infiltration. We found that BLCA patients with higher expression of CXCL12 and lower expression of CD3E had prolonged survival. Gene set enrichment analysis (GSEA) revealed that both CXCL12 and CD3E were enriched in immune-related pathways. We also discovered that stromal score and the level of CXCL12 were higher in luminal subtype, and immune score and the level of CD3E were higher in the basal subtype. Furtherly, we found that CXCL12 was associated with naive B cells, resting mast cell, M2 macrophages, follicular helper T cells, and dendritic cells. CD8+ T cells, CD4+ T cells, regulatory T cells (Tregs), and macrophages were correlated with CD3E. In conclusions, we found that CXCL12 and CD3E might serve as indicators of TME modulation in BLCA. Therapy targeting CXCL12 and CD3E had the potential as novel therapeutic strategy.

Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy

“…Blocking this axis seems to be a relevant strategy for BCa treatment as SDF-1 and CXCR4 are expressed in bladder tumor tissue [ 143 ]. Their expression is associated with tumor pT stage and grade [ 144 , 145 , 146 ] but also with poor patient OS [ 147 ]. Moreover, TCGA analysis demonstrated that SDF-1 gene expression positively correlates with M2-like TAMs [ 146 ], confirming the relationship between the SDF-1-CXCR4 axis and TAM recruitment in BCa.…”

“…Their expression is associated with tumor pT stage and grade [ 144 , 145 , 146 ] but also with poor patient OS [ 147 ]. Moreover, TCGA analysis demonstrated that SDF-1 gene expression positively correlates with M2-like TAMs [ 146 ], confirming the relationship between the SDF-1-CXCR4 axis and TAM recruitment in BCa. Despite that, no preclinical study has evaluated the effect of blocking TAMs via the SDF-1-CXCR4 pathway in BCa.…”

Comprehensive Exploration of Tumor Microenvironment Modulation Based on the ESTIMATE Algorithm in Bladder Urothelial Carcinoma Microenvironment

“…However, whether the TME status of BLCA contributes to the prediction of BLCA prognosis remains unknown. Recent studies have been reported that the immune and stromal scores in the TME could be calculated by ESTIMATE algorithms, which contributes to provide a novel insight into the development of immune treatment ( 21 ). Currently, immunotherapy for TME has been shown to improve BLCA treatment ( 2 ).…”

Identification of the Immune-Related Genes in Tumor Microenvironment That Associated With the Recurrence of Head and Neck Squamous Cell Carcinoma

“…Anti-CCR5 therapy in cancer patients can effectively target tumor immune cells in colorectal cancer metastasis ( Jiao et al, 2019 ). As an indicator of bladder cancer TME regulation, CD3E is closely related to immune infiltration ( Liu Y. et al, 2021 ). The tumor antigen-specific CD4 + T cells in cancer immunity are a key strategy for tumor prognosis and treatment ( Protti et al, 2014 ).…”