Interleukin-23 receptor signaling in regulatory T cells in a mouse model of inflammation-associated cancer.

ABSTRACT: The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal carcinogenesis (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC. In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, Foxp3YFP-Cre), and mice harboring a Treg cell-specific deletion of IL-23 (Il23rΔTreg). Il23rΔTreg mice had increased dysplasia compared to WT mice associated with decreased tumor-infiltrating macrophages. The role of Treg cell IL-23R in sporadic CRC was examined via orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. In the sporadic cancer model, Il23rΔTreg mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of Il23rΔTreg mice had a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4+ T cells. This data suggests that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4+ T cells that in turn promotes pro-inflammatory macrophages to clear tumors. These findings further support and highlight the importance of selecting a physiologically relevant model based on the type of cancer in which to evaluate the role of specific genes in late tumorigenesis. Finally, single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that IL23R was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE240707 | GEO | 2024/02/28

REPOSITORIES: GEO