Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment

Abstract

Single-cell sequencing technologies have noteworthily improved our understanding of the genetic map and molecular characteristics of bladder cancer (BC). Here we identify CD39 as a potential therapeutic target for BC via single-cell transcriptome analysis. In a subcutaneous tumor model and orthotopic bladder cancer model, inhibition of CD39 (CD39i) by sodium polyoxotungstate is able to limit the growth of BC and improve the overall survival of tumor-bearing mice. Via single cell RNA sequencing, we find that CD39i increase the intratumor NK cells, conventional type 1 dendritic cells (cDC1) and CD8 + T cells and decrease the Treg abundance. The antitumor effect and reprogramming of the tumor microenvironment are blockaded in both the NK cells depletion model and the cDC1-deficient Batf3−/− model. In addition, a significant synergistic effect is observed between CD39i and cisplatin, but the CD39i + anti-PD-L1 (or anti-PD1) strategy does not show any synergistic effects in the BC model. Our results confirm that CD39 is a potential target for the immune therapy of BC.

An Evaluation of the Tumor Microenvironment through CALR, IL1R1, IFNB1, and IFNG to Assess Prognosis and Immunotherapy Response in Bladder Cancer Patients

“…The high-risk group (50% vs. 50%) had significantly shorter survival times than the low-risk group ( Figure 6D ), corroborating the previous results ( Figure 3D, E ). More importantly, we found a significant positive correlation between the risk-score and CD39, a molecule we previously confirmed to be associated with immune suppression 14 . Additionally, the risk score showed a significant positive correlation with immune exhaustion (CD8+LAG3+), while having a negative correlation with CD8+ T cell infiltration (the IRS scores are based on our previous research 14 ).…”

“…More importantly, we found a significant positive correlation between the risk-score and CD39, a molecule we previously confirmed to be associated with immune suppression 14 . Additionally, the risk score showed a significant positive correlation with immune exhaustion (CD8+LAG3+), while having a negative correlation with CD8+ T cell infiltration (the IRS scores are based on our previous research 14 ). However, there was no correlation with tumor volume and T-stage ( Figure 6E-I ).…”

“…We obtained TCGA data from https://portal.gdc.cancer.gov/ and GEO data from https://www.ncbi.nlm.nih.gov/geo/. Access our single-cell sequencing data 14 at https://ngdc.cncb.ac.cn/gsa-human/browse/HRA000212 or https://www.ncbi.nlm.nih.gov/bioproject/PRJNA662018/.…”

SPI1‐mediated CXCL12 expression in bladder cancer affects the recruitment of tumor‐associated macrophages

“…Even though TAMs and their precursors account for the largest population of the inflammatory cells and constitute up to 50% of several human solid tumors, 32 whether the E:T ratio (10:1) used in the co‐culture experiments is biologically relevant needs to be explored in our subsequent studies. In addition, subcutaneous injection was used for animal modeling and only proinflammatory cytokines were examined in the serum to assess the TAM recruitment, further intravesical implantation in in vivo BC models 10 and flow cytometry analysis within the tumor tissues 33 are needed to support our conclusion.…”

Identification of Biomarker Genes in the Early Immune State of Bladder Epithelial Cancer

“…Regulatory T (Treg) cells, distinguished by the expression of the transcription factor forkhead box protein P3 (FOXP3), represent a unique subpopulation of CD4 + T cells. Tregs, capable of promoting tumor progression, trigger multiple immunosuppressive mechanisms, both by direct cell-to-cell contact and through the secretion of various cytokines [27][28][29][30]. We conducted an analysis on the in ltration of immune cells in bladder epithelial cancer and its association with in ammatory factors.…”