Il22ra2-high cDC2 associate with TH17 remodeling in AOM/DSS colonic tumorigenesis

Colorectal cancer (CRC) arises within a chronically inflamed and microbiota-rich environment, where epithelial repair programs and immune surveillance are tightly interwoven. Among cytokines orchestrating this crosstalk, IL-22 promotes epithelial regeneration and barrier integrity but, through sustained STAT3 activation in chronic settings, can also fuel tumor growth. At mucosal barriers, CD4⁺ T helper 17 (TH17) cells represent a major source of IL-22. Within this environment, dendritic cells (DCs) orchestrate tissue homeostasis by integrating microbial, metabolic, and cytokine-derived cues to regulate T cell-mediated immunity. Conventional type 2 DCs (cDC2) are emerging as key regulators of adaptive immunity at barrier sites, but their contribution to the immunological architecture of CRC remains only partially understood. Using an AOM/DSS-driven model of colonic tumorigenesis combined with single-cell transcriptomics, we identify a specialized cDC2 subset characterized by high expression of IL-22 binding protein (IL-22BP, also known as Il22ra2), which emerges as top differentially expressed gene. IL-22BP is a soluble decoy receptor that specifically binds IL-22 and prevents its engagement of membrane-bound IL-22R1; in the intestine, IL-22BP expression is known to be downregulated during acute tissue damage. In addition to Il22ra2 expression, this cDC2 subpopulation displays an inflammatory and tissue-adapted transcriptional profile and co-expresses high levels of Il23a, positioning it as a potential source of IL-23 in colonic cancer, a cytokine required for the expansion and maintenance of TH17 cells. In parallel, we observe by spectral flow cytometry a marked remodeling of both CD4⁺ and CD8⁺ T cell compartments, with a pronounced accumulation of CD4⁺ TH17 cells and RORgT⁺ T regulatory (RORgT⁺ Treg) cells. Altogether, our data uncover a previously unrecognized link between IL-22BP⁺, Il23a⁺ cDC2 and the IL-22 / IL-23 / TH17 axis in the colonic tumor microenvironment, pointing to a specialized function of this subset in T cell immunity that warrants further investigation in CRC.