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An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc-mutation-driven intestinal tumorigenesis

Interleukin-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...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612821/
https://www.ncbi.nlm.nih.gov/pubmed/35658010
http://dx.doi.org/10.1126/sciimmunol.abn0175
Descripción
Sumario:Interleukin-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 anti-tumor responses. Ablation of IL-25-signalling 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 anti-tumor immunity. Therapeutic antibody-mediated blockade of IL-25-signalling decreased intratumoral ILC2s, MDSCs and adenoma/adenocarcinoma, while increasing anti-tumor adaptive T cell and IFNγ-mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33, and ILC2s in cancer cannot be generalized. The pro-tumoral nature of the IL-25-ILC2 axis in CRC highlights this pathway as a novel therapeutic target against CRC.