Journal
SCIENCE IMMUNOLOGY
Volume 7, Issue 72, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abn0175
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Funding
- UK Medical Research Council [U105178805]
- Wellcome Trust [100963/Z/13/Z, 220223/Z/20/Z]
- Cambridge School of Clinical Medicine MBPhD Programme
- European Union [896454]
- Rosetrees Trust
- International Journal of Experimental Pathology
- Wellcome Trust [100963/Z/13/Z, 220223/Z/20/Z] Funding Source: Wellcome Trust
- Marie Curie Actions (MSCA) [896454] Funding Source: Marie Curie Actions (MSCA)
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Intestinal IL-25-activated ILC2s create a cancer-permissive microenvironment, associated with reduced survival and increased MDSCs in colorectal cancer patients. Ablation of IL-25 signaling reduces tumors and extends lifespan, while therapeutic antibody blockade enhances antitumor immunity.
Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection and are associated with inappropriate allergic reactions. IL-33-activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25-activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival and increased IL-25R-expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired antitumor responses. Ablation of IL-25 signaling reduced tumors, virtually doubling life expectancy in an Apc mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress antitumor immunity. Therapeutic antibody-mediated blockade of IL-25 signaling decreased intratumoral ILC2s, MDSCs, and adenoma/adenocarcinoma while increasing antitumor adaptive T cell and interferon-gamma (IFN-gamma)-mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33 as well as ILC2s in cancer cannot be generalized. The protumoral nature of the IL-25-ILC2 axis in CRC highlights this pathway as a potential therapeutic target against CRC.
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