TRYPTOPHAN-DERIVED MICROBIAL METABOLITES PROMOTE NKT22 PRO-TUMORIGENIC FUNCTIONS IN COLITIS ASSOCIATED COLORECTAL CANCER PATIENTS

Patients with IBD have an elevated risk of developing CAC. IL-22, a cytokine involved in epithelial cell proliferation and survival, is also linked to tumor formation. It is secreted by various immune cells, including tissue-resident iNKT cells. In IBD, iNKT cells exhibit either pro-inflammatory or tolerogenic activities depending on the microbiota, raising questions about their role in CAC development. To investigate this, high-dimensional single-cell cytometry, metagenomics, RNAseq, spatial immunophenotyping, transcriptomics, ex vivo and in vitro experiments were conducted. Metabolomics identified microbial-derived molecules activating iNKT cells. Mechanisms were studied using CAC murine models with or without functional iNKT cells. Increased NKT22 infiltration was observed in CAC tissues, along with enrichment of Odoribacter, a bacterium linked to tryptophan metabolism. Metabolites from Odoribacter stimulated iNKT cells to produce IL-22 via AhR activation. Metabolomic analysis confirmed elevated tryptophan metabolites in Odoribacter supernatants, driving NKT22 differentiation in vitro and in vivo. Administration of Odoribacter supernatant or purified metabolites enhanced tumorigenesis in CAC mouse models, but not in iNKT-deficient mice. Spatial proteomics and transcriptomics of human CAC tissues corroborated microbiota-dependent functional changes in iNKT cells near cancer cells. In CAC patients, iNKT cells are key IL-22 producers, activated by microbiota-derived metabolites linked to tryptophan metabolism and AhR signaling. This interaction between NKT22 cells and the microbiota likely plays a pivotal role in CAC progression.