Decoding hepatobiliary-specific immune gene patterns in gastrointestinal cancers via gene ontology fingerprints, multi-omics, and experimental integration.

BACKGROUND: Gastrointestinal (GI) cancers are characterized by high malignancy and poor prognosis. Tumors in different locations exhibit both commonalities and differences. Although immunotherapy has made progress in some GI cancers, the specific immune-related patterns in hepatobiliary tumors have not yet been fully elucidated. METHODS: Using our developed explainable gene ontology fingerprint (XGOF) method, a GI cancer GOF was established. By integrating omics data from 20 hepatocellular carcinoma (HCC) and 15 intrahepatic cholangiocarcinoma (ICC) tissues in our clinic with public databases, immune-related patterns specifically expressed in hepatobiliary tumors were identified via RNA, protein, methylation, tumor microenvironment (TME) analysis, and experimental verification. RESULTS: XGOF showed that GI cancers are related to diverse immune functions, especially macrophage migration. Compared to others, hepatobiliary tumors exhibit distinct patterns of gene expression, mutation, and methylation. Seven genes (APOA1, LBP, FGA, C9, APCS, ARG1, and MBL2) were identified as immune-related genes specifically decreased in hepatobiliary cancer. The impact of APOA1 on TME, prognosis, and genomic landscape in HCC was explored in prior research. In this work, the experiment confirmed the down-regulation of six genes in cancerous tissues. Moreover, LBP promoter methylation was elevated in cholangiocarcinoma. Single-cell analysis revealed downregulated immune genes in hepatocytes of HCC and cholangiocytes of ICC, enriched in humoral immunity and complement pathways. Additionally, the macrophage migration inhibitory factor (MIF) pathway was identified as a key signal in interactions between ICC tumor cells and microenvironmental cells. CONCLUSION: This study identified immune-related gene patterns in hepatobiliary cancer, contributing to the discovery of novel immunotherapy targets and tumor biomarkers for future research.