IL4I1 and tryptophan metabolites enhance AHR signals to facilitate colorectal cancer progression and immunosuppression.

OBJECTIVE: The molecular mechanisms underlying tumor progression and drug resistance in colorectal cancer remain to be fully understood. Recent studies have reported a pro-tumorigenic role of an amino acid oxidase named interleukin-4-induced-1 (IL4I1). Here, we investigate the role and molecular mechanism of IL4I1 in colorectal cancer.

METHODS: We employed bioinformatics analysis and experimental validation by using clinical samples and a variety of cell-based assays, including western blot, Transwell assay, patient-derived organoid culture, Immunofluorescence assay, T cell cytotoxicity assay, and flow cytometry.

RESULTS: Bioinformatics analysis showed a higher IL4I1 expression in colorectal cancer tissues than in normal tissues. In vitro overexpression of IL4I1 enhanced the proliferation, migration, and invasion of colorectal cancer cells. In addition, deprivation of Tryptophan (Trp) in cultural medium diminished the oncogenic effect of IL4I1. Furthermore, we observed a positive correlation of IL4I1 and AHR expression in the TCGA database of colorectal cancer. We also detected an enhanced cytoplasmic expression and nuclear translocation of Aryl hydrocarbon receptor (AHR). Moreover, IL4I1 overexpression suppressed the cytolytic killing of tumor cells and enhanced T cell exhaustion. Finally, in the organoid culture model, we found that immunotherapy and SR-1 combination treatment could induce higher level of apoptosis than did the immunotherapy or SR-1 treatment alone.

CONCLUSION: we demonstrated that IL4I1 facilitated colorectal cancer progression and immunosuppression through tryptophan metabolism dependent on AHR activation.