UCN expresses differently in left-sided and right-sided colon cancer contributing to distinct immune microenvironment...

Urocortin (UCN), is found to be overexpressed in colorectal cancer (CRC) but its role in tumor immune microenvironment (TIME) remains unclear.

UCN expression was analyzed using RNA sequencing data from TCGA and detected in tumor samples from 18 patients with LC and 27 patients with RC. Tumor infiltrated T cells (TILs) were isolated from tumors and the exhaustion markers including PD-1, TIGIT, TIM-3 and LAG3 on CD8 + TILs were detected by flow cytometry. Correlations between UCN level and immunoregulatory factors were analyzed using Spearman correlation analysis. UCN was overexpressed in CRC cell lines and the CCL23 levels were detected by quantitative RT-PCR and enzyme-linked immunosorbent assay.

UCN was mainly overexpressed in Right-sided colon cancer (RC) and to be related to poor prognosis. Higher UCN level in tumors related to increased abundance of regulatory T cells and upregulated exhaustion markers in CD8 + T cells. UCN is positively correlated with CCL23 level in CRC and mainly upregulated in RC samples. Overexpression of UCN in HCT116 and HT-29 cells upregulated CCL23 expression and promoted CCL23 secretion. CD8 + T cells cultured with medium from UCN overexpressed CRC cells exhibited exhaustion phenotype with increased expression of CTLA-4, PD-1, TIGIT, TIM-3 and LAG-3, which was restored by CCL23 antibody.

This study successfully constructed the correlation between UCN overexpression and immunosuppressive TIME formation in CRC, providing a candidate target for new immunotherapy against CRC development.