IL-17RA signaling provides dual tumor-suppressor function during late-stage colorectal carcinogenesis
Expression of interleukin (IL)-17 family cytokines is associated with tumor-promoting inflammation. We found that low expression of IL17RA associated with worse prognosis in late-stage colorectal cancer (CRC) patients. Deletion of Il17ra in intestinal epithelial cells (IECs) in a murine model of CRC enhanced epithelial-to-mesenchymal transition (EMT) via increased expression of the epidermal growth factor receptor and subsequent activation of the kinase Src. Yet, these mice were protected from metastatic disease; Il17ra deletion impaired intestinal barrier function and enhanced systemic fungal invasion and associated immunity. However, in macrophages, IL-17RA was required for spleen tyrosine kinase (Syk) activation upon fungal-induced dectin-1 engagement, and Il17ra ablation impaired IL-18 release and protective CD8<sup>+</sup> T cell-mediated anti-tumor immunity. Combining recombinant IL-17 and heat-killed Candida albicans rendered colorectal tumors sensitive to α-PD-1 treatment in a model of microsatellite stable (MSS) CRC. Thus, IL-17RA engages two distinct tumor-suppressive mechanisms in CRC, linking EMT and fungal-induced anti-tumor immunity during tumor progression.
Authors
- Florian R. Greten (ORCID: https://orcid.org/0000-0002-3928-6080)
- Asude Callak Kirisözü
- Marina Pešić (ORCID: https://orcid.org/0009-0000-6315-841X)
- Ari Waisman (ORCID: https://orcid.org/0000-0003-4304-8234)
- Dominic Denk (ORCID: https://orcid.org/0000-0002-4887-1492)
- Mallika Ramakrishnan (ORCID: https://orcid.org/0000-0003-3144-2824)
- Kathleen Mohs
- Charles Pallangyo (ORCID: https://orcid.org/0000-0001-9476-2062)
- Ezgi Özkurt (ORCID: https://orcid.org/0000-0002-6643-240X)
- Falk Hildebrand (ORCID: https://orcid.org/0000-0002-0078-8948)
- Annie Pardo (ORCID: https://orcid.org/0000-0003-2168-9073)
- Kilian B. Kennel (ORCID: https://orcid.org/0000-0002-7375-1249)
- Birgit Ritter (ORCID: https://orcid.org/0000-0002-0315-1301)
- Melek C. Arkan
- Claire Conche (ORCID: https://orcid.org/0009-0008-6171-8688)
- Esther Engel
- Fatih Ceteci
Institutions
- Goethe University Frankfurt (DE)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- Quadram Institute (GB)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- University Hospital Frankfurt (DE)
- Georg Speyer Haus (DE)
- Frankfurt Cancer Institute (DE)
Publication Details
- Journal
- Immunity
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1016/j.immuni.2025.02.005
- Citations
- 10
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 10.45
Funders
- European Research Council