Abstract
Background: CD8+ T cells in the tumor microenvironment are crucial for antitumor effects. Boosting their infiltration can significantly enhance the efficacy of antitumor immunotherapy. However, the precise contribution of the epigenetic regulator lysine-specific demethylase 6B (KDM6B) to colorectal cancer (CRC) immunity remains elusive.
Methods: KDM6B expression was detected in adjacent and CRC tissues or normal and cancer cells. Mouse models of CRC were established to assess the impact of KDM6B on tumor progression. The infiltration of CD8+ T cells was detected by IHC and a transwell assay. RT-qPCR, western blotting or flow cytometry were used to detect the effect of KDM6B on PD-L1, CD8+ T-cell-attracting chemokines and p-STAT3 expression. ChIP-qPCR was performed to determine the H3K27me3 enrichment in the promoter regions of target genes PD-L1 and CD8+ T-cell-attracting chemokines. Finally, paricalcitol was combined with anti-PD-L1 antibodies to evaluate their anti-CRC effects.
Results: KDM6B was downregulated in CRC tissues and cells, but its overexpression successfully hindered CRC growth and liver metastasis. Mechanistically, the activation of demethylase activity and STAT3 signaling, leading to increased expression of CD8+ T-cell-attracting chemokines CCL5, CXCL9, and CXCL10, as well as enhanced PD-L1 expression in CRC cells. This ultimately resulted in increased infiltration of CD8+ T cells. Paricalcitol and anti-PD-L1 antibody therapy work together to achieve superior tumor elimination efficiency. Paricalcitol, combined with anti-PD-L1 antibodies, offered superior tumor elimination efficiency.
Conclusion: These findings suggest that KDM6B plays a positive role in regulating the immune microenvironment in CRC, potentially offering a theoretical basis for CRC immunotherapy.