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

The molecular mechanisms underlying tumor progression and drug resistance in colorectal cancer remain inclusive. Recent studies have reported a pro-tumorigenic role of an amino acid oxidase named interleukin-4-induced-1 (IL4I1). In the present study, we found higher IL4I1 expression in colorectal cancer tissues compared with normal tissues by TCGA database and immunohistochemistry. To explore the underlying mechanism of IL4Il in colorectal cancer progression, we overexpressed IL4I1 in HCT116 and MC38 colorectal cancer cell lines and found significantly enhanced proliferation, migration and invasion by IL4I1 overexpression. Deprived of Tryptophan (Trp) in cultural medium diminished the pro-tumor effect of IL4I1. Furthermore, we observed a positive correlation of IL4I1 and AHR expression in TCGA database of colorectal cancer. We detected enhanced nuclear translocation and cytoplasmic expression of AhR by fluorescent microscopy but this effect was inhibited by SR-1 treatment. Moreover, we found that IL4I1 further suppressed cytolytic killing of tumor cells, and enhanced T cell exhaustion in mouse model. Finally, in the murine xenograft model, we found chemoimmutherapy and SR-1 combined treatment could achieve superior outcomes with decreased tumor size and improved survival rate than that of chemoimmutherapy or SR-1 treatment alone. Also, AhR inhibition by SR-1 greatly reversed the IL4I1 overexpression induced chemoimmutherapy resistance in vivo. Taking together, we demonstrated a pro-tumorigenic role of IL4I1 both in vivo and in vitro and suggested that IL4I1 facilitated colorectal cancer progression and immunosuppression through tryptophan metabolism depend AhR activation.