Front Immunol. 2024 Jun 27;15:1428529. doi: 10.3389/fimmu.2024.1428529. eCollection 2024.

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized gastrointestinal cancer treatment, yet the absence of reliable biomarkers hampers precise patient response prediction.

METHODS: We developed and validated a genomic mutation signature (GMS) employing a novel artificial intelligence network to forecast the prognosis of gastrointestinal cancer patients undergoing ICIs therapy. Subsequently, we explored the underlying immune landscapes across different subtypes using multiomics data. Finally, UMI-77 was pinpointed through the analysis of drug sensitization data from the Genomics of Drug Sensitivity in Cancer (GDSC) database. The sensitivity of UMI-77 to the AGS and MKN45 cell lines was evaluated using the cell counting kit-8 (CCK8) assay and the plate clone formation assay.

RESULTS: Using the artificial intelligence network, we developed the GMS that independently predicts the prognosis of gastrointestinal cancer patients. The GMS demonstrated consistent performance across three public cohorts and exhibited high sensitivity and specificity for 6, 12, and 24-month overall survival (OS) in receiver operating characteristic (ROC) curve analysis. It outperformed conventional clinical and molecular features. Low-risk samples showed a higher presence of cytolytic immune cells and enhanced immunogenic potential compared to high-risk samples. Additionally, we identified the small molecule compound UMI-77. The half-maximal inhibitory concentration (IC50) of UMI-77 was inversely related to the GMS. Notably, the AGS cell line, classified as high-risk, displayed greater sensitivity to UMI-77, whereas the MKN45 cell line, classified as low-risk, showed less sensitivity.

CONCLUSION: The GMS developed here can reliably predict survival benefit for gastrointestinal cancer patients on ICIs therapy.

PMID:38994371 | PMC:PMC11236566 | DOI:10.3389/fimmu.2024.1428529