A Surprising Shift from Foe to Friend
Researchers from the Georg-Speyer-Haus in Frankfurt am Main, Germany, have uncovered a surprising twist in how inflammation influences colorectal cancer (CRC). In a study published in Immunity (DOI: 10.1016/j.immuni.2025.02.005), the team found that a protein called IL-17RA - receptor of inflammatory signaling known for fueling early-stage tumor growth - switches roles in advanced CRC, acting as a critical defense mechanism to block tumor spread and boost immunity.
Colorectal cancer remains a leading cause of cancer-related deaths, particularly in advanced stages. In recent years, the incidence of CRC has seen an alarming increase in young adults. Whereas numerous research findings have improved outcomes, many patients still do not respond to novel therapeutic approaches such as immunotherapy. Current research suggests that the inflammatory tumor microenvironment (TME), i.e. the area within and around the tumor also containing stroma and immune cells, and the microbiome (all local microbes, such as bacteria, fungi, viruses, and their genes), could hold the key to better understanding the heterogeneity of cancer and develop novel therapies.
Led by Prof. Florian Greten, the research team discovered that IL-17RA has a ‘Jekyll and Hyde’ effect in CRC. Early in the disease, IL-17RA promotes tumor growth, aligning with past clinical data. In later stages of CRC, however, IL-17RA becomes protective, improving survival. This shift occurs through two key mechanisms in the TME: IL-17RA blocks cancer cells from re-expressing EGFR, a growth factor receptor that is important for invasive growth and metastasis. At the same time, IL-17RA expression is required to activate the immune system in response to fungi in the gut, triggering immune responses that activate cancer-fighting T cells. While these findings highlight the stage-dependent importance of IL-17RA in both tumor cells and the immune system to limit cancer progression, they also indicate that fungal species can directly initiate anti-tumor immunity. Building on these findings, the researchers then stimulated the fungi-IL-17RA axis to sensitize colorectal tumors to immunotherapy.
‘Our study underscores the complex interplay between the tumor, the immune system, and the microbiome’, explains Dr. Dominic Denk, physician at Frankfurt University Medicine, Fellow of the Mildred Scheel Career Center Frankfurt and first author of the study. ‘By decoding how IL-17RA flips its role from tumor promotion to tumor suppression, we highlight the potential for future combination therapies for advanced CRC.’
Prof. Greten, director of the Georg-Speyer-Haus and spokesperson of the LOEWE center Frankfurt Cancer Institute, emphasizes the bigger picture: ‘Our data highlight an unexpected contribution of IL-17RA signaling in EMT;and on the other hand a central role in sensing of fungi, thus indicating the broad impact of our findings that clearly go beyond colorectal cancer.’
These results strongly suggest that enhancing IL17 signaling has clinical potential in enhancing anti-tumor immunity in invasive tumors.
Publication
Denk et. al.
IL-17RA signaling provides dual tumor suppressor function during late-stage colorectal carcinogenesis.
Immunity, 2025.
DOI: 10.1016/j.immuni.2025.02.005
Contact
Prof. Dr. Florian R. Greten
Georg-Speyer-Haus Institut für Tumorbiologie und experimentelle Therapie
Paul-Ehrlich-Str. 42-44
60596 Frankfurt am Main
+4969 63395-232