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- Title
An innate IL-25–ILC2–MDSC axis creates a cancer-permissive microenvironment for Apc mutation–driven intestinal tumorigenesis.
- Authors
Jou, Eric; Rodriguez-Rodriguez, Noe; Ferreira, Ana-Carolina F.; Jolin, Helen E.; Clark, Paula A.; Sawmynaden, Kovilen; Ko, Michelle; Murphy, Jane E.; Mannion, Jonathan; Ward, Christopher; Matthews, David J.; Buczacki, Simon J. A.; McKenzie, Andrew N. J.
- Abstract
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-γ (IFN-γ)–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. ILC2s help tumors: Group 2 innate lymphoid cells (ILC2s) protect against parasitic infections and are implicated in allergies, yet their role in antitumor immunity remains unclear. Here, Jou et al. used various genetic mouse models to study the roles of ILC2s in colorectal cancer (CRC). They found that ILC2s were linked to an immunosuppressive tumor microenvironment, where deletion of these cells led to less CRC tumor burden. ILC2s were specifically responding to high IL-25 expression in CRC tumors, and in turn inducing immunosuppressive myeloid-derived suppressor cells. Therapeutically blocking the IL-25 receptor on ILC2s lowered tumor burden and led to more favorable antitumor immune responses. Thus, in response to IL-25 in the tumor microenvironment, ILC2s help to establish a protumorogenic immune microenvironment in CRC.
- Publication
Science Immunology, 2022, Vol 7, Issue 72, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abn0175