Abstract
The composition of immune infiltrates strongly affects the prognosis of patients with colorectal cancer (CRC). Interleukin (IL)-33 and regulatory T cells (Tregs) in the tumor microenvironment have been separately implicated in CRC; however their contribution to intestinal carcinogenesis is still controversial. Here, we reveal that IL-33 signaling promotes CRC by changing the phenotype of Tregs. In mice with CRC, tumor-infiltrating Tregs preferentially upregulate IL-33 receptor (ST2), and IL-33/ST2 signaling positively correlates with tumor number and size. Transcriptomic and flow cytometry analyses demonstrate that ST2 expression induces a more activated and migratory phenotype in FOXP3+ Tregs, which favors their accumulation in the tumor environment. Consequently, genetic ablation of St2 reduces Treg infiltration and concomitantly enhances the frequencies of effector CD8+ T cells, thereby restraining CRC. Mechanistically, IL-33 curtails IL-17 production by FOXP3+ Tregs and inhibits Th17 differentiation. In humans, numbers of activated ST2-expressing Tregs are increased in blood and tumor lesions of CRC patients, suggesting a similar mode of regulation. Together, these data indicate a central role of IL-33/ST2 signaling in shaping an immunosuppressive environment during intestinal tumorigenesis. Blockade of this pathway may provide a strategy to modulate the composition of CRC immune infiltrates.
Highlights
IntroductionInterleukin-33 (IL-33) is an IL-1 family member, which mediates its biological effects via binding to a heterodimeric receptor complex formed by IL-1RL1 (or ST2) and its co receptor, IL-1 receptor accessory protein (IL-1RAP).[1] IL-33 is constitutively expressed as a nuclear factor by a broad range of cell types, including fibroblasts, epithelial, and endothelial cells, in mucosal tissues.[2]
Interleukin-33 (IL-33) is an IL-1 family member, which mediates its biological effects via binding to a heterodimeric receptor complex formed by IL-1RL1 and its co receptor, IL-1 receptor accessory protein (IL-1RAP).[1]
Upregulation of Il33 and St2 expression in murine colorectal cancer (CRC) IL-33 expression has been shown to become upregulated upon neoplastic transformation of human and murine colonic tissues and to promote intestinal tumorigenesis.[15,16]
Summary
Interleukin-33 (IL-33) is an IL-1 family member, which mediates its biological effects via binding to a heterodimeric receptor complex formed by IL-1RL1 (or ST2) and its co receptor, IL-1 receptor accessory protein (IL-1RAP).[1] IL-33 is constitutively expressed as a nuclear factor by a broad range of cell types, including fibroblasts, epithelial, and endothelial cells, in mucosal tissues.[2]. Upon tissue injury, cell stress or necrosis IL-33 can be released to act as an alarmin by activating cells of lymphoid and myeloid origin.[3]. The IL-33/ST2 pathway was originally described to play a key role in type 2 immunity via activation of ST2-expressing T helper 2 (Th2) cells.[4] Besides this Th2-promoting function of IL-33, recent murine studies provided evidence for a pivotal role of the IL-33/. IL-33 directly acts on ST2+ FOXP3+ Tregs and stimulates IL-2 production by CD11c+ dendritic cells, which in turn facilitate the expansion of
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