Dominic Denk
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domdenkmd.bsky.social
Dominic Denk
@domdenkmd.bsky.social
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MD | physician-scientist | GI-oncology and immunology. Likes ducks.
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domdenkmd.bsky.social
This means fungi can be protective to instigate an anti-tumor immunity⚡!

When we now use heat-killed Candida (a fungal species) and IL-17A (the signal that binds to IL-17RA) in combination in vivo, we can blunt tumor growth!
Co-treatment of IL-17 (activation of IL-17RA) with heat-killed Candida albicans (HKCA, activating the dectin-syk axis in macrophages) sensitizes tumors to immunotherapy. Co-treatment is represented by the green line, showing the strongest tumor repression. Immunotherapy alone (black) does not limit tumor growth in this model (as we have also observed in PMID: 36351375). It is important to note that we do not suggest that it works the same way in humans! Many further studies are required to assess whether activating Dectin signaling (in any way!) is a feasible approach
February 28, 2025 at 7:49 PM
domdenkmd.bsky.social
2)

On myeloid cells, IL-17RA expression is critical to augment Dectin-1 mediated sensing of #fungal populations. This results in inflammasome activation and IL-18 maturation.

So: Fungal populations🍄 induce CD8-mediated antitumor immunity, but this requires IL-17RA!
The effect of IL-17RA on macrophages. Fungal populations such as yeast are sensed by dectin-1, activating Syk. This induces cytokine production such as IL-1b and IL-18. Our data suggests that IL17RA on macrophages is required to robustly activate the dectin-Syk axis. IL-18 elicits T cell-mediated antitumor immunity.
February 28, 2025 at 7:49 PM
domdenkmd.bsky.social
1) On tumor cells, loss of IL-17RA protects from epithelial-mesenchymal transition, limiting invasion.

IL-17RA appears to be critical to limiting EGFR shuttling back to the cell's surface, thereby blunting Src signaling.
The effect of IL17RA on intestinal epithelial cells. Our data suggests that IL17RA is critical to limit recycling of EGFR to the cell surface, thereby putting a lid on pro-invasive signaling. Without IL17RA, EGFR availability and subsequent signaling are unleashed - resulting in activation of Src and epithelial-to-mesenchymal transition (EMT).
February 28, 2025 at 7:49 PM
domdenkmd.bsky.social
Using a model of invasive colorectal cancer, we could see a time-dependent effect of IL-17RA.

(1) IL17-RA expression fosters tumor growth early on,

(2) but when tumors become invasive, IL17-RA appears protective.

Why is that?
Experimental model of invasive CRC: G-H Deletion of IL17RA in intestinal epithelial cells results in less invasion in early tumor stages, here in a experimental model of CRC at 12 weeks. I-J At late stages (in this model at 18 weeks) when tumors have become fully invasive, deletion of IL17RA results in MORE tumor invasion. In other words: IL17RA is surprisingly protective in late stages!
February 28, 2025 at 7:49 PM
domdenkmd.bsky.social
We were presented with a paradox:

➡️We know that inflammatory IL-17 promotes tumorigenesis in enterocytes, and in early stages of CRC, a Th17 signature is considered unfavorable.

⚡Yet, in late-stage disease, expression of its receptor IL-17RA is associated with better prognosis in patients.
IL-17RA has opposing effects in colorectal cancer, depending on the disease stage: Previous experimental evidence and population data suggest that it promotes early tumorigenesis, thereby associating with a worse outcome in EARLY cancer stages. Yet, in an ADVANCED and metastatic setting, IL-17RA expression is associated with better survival.
February 28, 2025 at 7:49 PM