Abstract: The immune escape mechanism of intrahepatic cholangiocarcinoma (iCCA) is still unclear, and there is a lack of effective intervention strategies in the clinic. The project applicant previously found through analysis of clinical samples and single-cell data that myeloid-derived suppressor cells (MDSC) in the iCCA microenvironment highly expressed the immune checkpoint VISTA, and its enrichment was associated with poor prognosis in patients, and enhanced the immunosuppressive activity of regulatory T cells (Treg) through the VISTA/PSGL-1 axis. Metabolomics analysis showed that abnormal lactate accumulation in the tumor microenvironment drives MDSC to VISTA⁺ phenotype transformation by inducing histone H4K12 lactylation (H4K12la). Based on the previous work, this study intends to reveal the key modifying enzymes that regulate H4K12la and clarify the key transcription factors involved in VISTA transcription, so as to systematically analyze the regulatory mechanism of the H4K12la-VISTA/PSGL-1 axis on the MDSC-Treg immunosuppressive network. This study will also use patient-derived organoids, humanized mice and other models to evaluate the synergistic efficacy of targeting key regulatory molecules in combination with PD-1 monoclonal antibodies, providing a scientific basis for the development of new iCCA immunotherapy strategies based on the "H4K12la-VISTA+MDSC-Treg" axis.
Funding Source: This work was supported by the Key Research & Development Plan of Zhejiang Provincial Department of Science and Technology (No. 2024C03051), and the National Key R&D Program of China (2021YFA1100500), the Major Research.
