CD39 Inhibition Alters Tumor Microenvironment: Single-Cell Sequencing Insights
Summary
Through advancements in single-cell sequencing, researchers have deepened insights into the genetics and molecular features of bladder cancer. They pinpointed CD39 as a promising therapeutic avenue via single-cell analysis. When CD39 was inhibited using sodium polyoxotungstate, there was notable suppression of bladder cancer growth and improved survival rates in mice. This inhibition altered the tumor's environment by increasing specific immune cells while reducing Treg cell presence. The positive outcomes, however, were hindered when certain immune cells were depleted. Interestingly, while CD39 inhibition worked synergistically with cisplatin, combining it with anti-PD-L1 or anti-PD1 yielded no synergistic benefits, underscoring CD39's potential in bladder cancer immune therapy.
Research Criteria
The publication delves into unraveling the molecular intricacies behind the variability in bladder cancer. Through single-cell RNA analysis on both tumor and adjacent tissues from those afflicted, the researchers aimed to distinguish the unique elements and surrounding conditions among varying molecular classifications.
Sample Type
The samples used for the single-cell experiments were 8 tumor samples and 3 paratumor samples from bladder cancer patients.
Result—CD39 is Overexpressed in BC and is Mostly Found in the Tumor Stroma
Researchers focused on bladder cancer (BC), CD39 was identified as a significant marker due to its notable overexpression in the tumor stromal region. Analysis of previous data pinpointed CD39 as a key immune checkpoint associated with patient progression. When categorizing cells from BC and adjacent tissues, a higher abundance of immune cells was observed in paracancerous tissues. Furthermore, CD39 was predominantly expressed in endothelial cells, smooth muscle cells, and fibroblasts. Notably, BC tissues exhibited a markedly higher CD39 expression than normal bladder tissues, and elevated CD39 levels were linked to worse patient outcomes.
Fig.1 CD39 expression pattern and function1.
Result—CD39i Induced cDC1 Expansion
In this study, dendritic cells (DCs) were reclustered, revealing six distinct subgroups. A notable observation was the significant increase in the cDC1 and cDC1-proliferating (cDC1-p) proportions following CD39i treatment, contrasting the decrease in other DC subpopulations. Interestingly, this alteration in proportion did not correspond with a change in the functional genes of each cell subgroup. CD39i appeared to specifically augment the cDC1 and cDC1-p numbers without directly impacting the DCs' function. Additionally, the monocyte-macrophage lineage displayed heightened heterogeneity, yet CD39i treatment did not influence the proportions or functional genes of these cell subgroups. This underscores CD39i's selective effect on expanding cDC1 without altering the functional attributes of the involved cells.
Fig.2 After CD39i therapy, the proportion of DC subpopulations and mononuclear macrophage subpopulations altered1.
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Reference
- Liu, Lilong, et al. "Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment." Nature Communications 13.1 (2022): 6740.
