Evaluation of colorectal cancer in ulcerative colitis reveals key immune factors during its malignant transformation

Abstract BACKGROUND & AIMS: Ulcerative colitis (UC) is linked to an increased risk of colitis-associated colorectal cancer (CAC), which accounts for approximately 15% of UC-related deaths. Despite this significant impact on patients, the mechanism behind how UC promotes cancer development remains unknown. The present study aims to investigate alterations in the immune microenvironment during the malignant transformation of UC, shedding light on the underlying mechanisms of UC carcinogenesis. METHODS We collected single-cell transcriptome samples of 41 healthy samples, 45 UC samples, and 148 colorectal cancer(CRC) samples from public databases. Using the UC-CRC signature, we were able to screen for CAC-like samples. Based on those datasets, several bioinformatics analyses were performed on 228,538 immune cells to evaluate the immune microenvironment from UC to CAC. RESULTS Using predefined UC-CRC signature, we screened 14 CAC-like samples and revealed an immune remodeling process from healthy tissue to UC and CAC-like samples, particularly involving the VEGFA_Macro cells and Treg cells. VEGFA_Macro cells was significantly enriched in UC and CAC-like samples, showed a phenotype alteration during disease progression, and expressed more inflammation-related genes and signal pathways. Additionally, the proportion of Treg cells gradually increased with disease progression, potentially promoting an immunosuppressive microenvironment. Comparative analysis of the immune microenvironment between CAC-like and sporadic CRC(sCRC) samples revealed higher levels of myeloid cells but reduced CD8 + T cells in CAC-like samples. Finally, we simplified the UC-CRC signature for ease of clinical use in screening CAC-like samples. CONCLUSIONS Our results may help improve the understanding dynamic change of immune microenvironment from UC to CAC and provide clues for further exploration of strategies to prevent carcinogenesis of UC.