Abstract
Background:
Pancreatic cancer, recognized as a refractory tumor, has an overall survival rate of less than 10%, and its mortality rate continues to rise. Due to the low immune activity induced by its unique tumor microenvironment, pancreatic cancer is classified as a "cold" tumor and is insensitive to current immunotherapies. However, little is still known about the identification and functional mechanisms of key regulatory molecules in the formation of "cold" tumors.
Methods:
In this study, we identified the pancreatic ductal cell niche through single-cell sequencing. By calculating CNV scores using inferCNV to distinguish malignant from non-malignant cells and analyzing differences in transcriptional levels, we constructed a 15-gene model. The inhibitory effect of UBE2H on the immune microenvironment was studied through single-cell sequencing analysis, including the inhibition of T cell function, impairment of antigen presentation in macrophages and neutrophils, and activation of neutrophil extracellular traps (NETs).
Results:
Our results revealed the presence of a UBE2H+ cell population within the pancreatic ductal cell niche, primarily observed in pancreatic cancer samples. Notably, single-cell sequencing analysis of UBE2H overexpression revealed an enhanced T cell PD-L1 interaction axis and a downregulation of antigen presentation pathways in macrophages and neutrophils (antigen processing and presentation, macrophage activation, and neutrophil activation). Further in vivo experiments confirmed that high UBE2H expression promotes tumor progression, leading to increased T cell exhaustion (PD1) and decreased activation (CD69, GZMB, IFNR) in the immune microenvironment, impaired antigen presentation of macrophages and neutrophils (H2Kb, I-Ab, I-A/E), and increased neutrophil extracellular trap formation (MPO, NE, CITH3).
Conclusions:
This study revealed the presence of a UBE2H+ cell population within the pancreatic ductal cell niche and analyzed the inhibition of UBE2H on the immune microenvironment of pancreatic cancer through single-cell sequencing and in vivo experiments, providing important clues for the formation of "cold" tumors in pancreatic cancer and opening new directions for exploring new treatment strategies.