Slater Clay

Macrophage MR1 antigen presentation promotes MAIT cell immunity and lung microbiota modulation
www.science.org/doi/10.1126/...
@science.org @thedohertyinst.bsky.social @hay-mish.bsky.social

Thanks Andy! 🤞

This was a team effort. Big thanks to all co-authors and collaborators @theGarrettLab.bsky.social, @JenTekle.bsky.social, @edreesrashan.bsky.social, @mvhlab.bsky.social, Yeun Shin, and Jon Clardy. (10/10)

Key takeaway:
Exogenous AcAc boosts anti-tumor MAIT cells by generating 5-OP-RU. This highlights a novel AcAc-MR1-MAIT axis with translational potential for CRC. (9/10)

How? Here’s the twist:
With the Clardy lab @harvardmed.bsky.social, we discovered that AcAc exposed to ambient oxygen spontaneously generates methylglyoxal, which is an important precursor in the formation of 5-OP-RU. (8/10)

This suggested AcAc generates an MR1 ligand, but what could it be?
This is where things got interesting. With help from @edreesrashan.bsky.social and @mvhlab.bsky.social, we found that AcAc and 5-A-RU form the potent MR1 ligand 5-OP-RU. (7/10)

MR1 presents metabolites to MAITs and its expression is regulated by antigen, so: does AcAc affect MR1 expression?
Yes! AcAc increased surface MR1 in both human PBMCs and mouse tumors, especially on monocytes- hinting they’re key in activating MAITs. (6/10)

How does AcAc enhance anti-tumor MAIT cells?
In cultures with human cells, AcAc expanded MAIT cells and increased their tumor killing- but only in the presence of 5-A-RU (a microbe-derived riboflavin intermediate), and if MR1 was able to present antigen. (5/10)

scRNA-seq & flow cytometry showed AcAc increases tumor MAIT cells and enhances their expression of cytotoxic effectors like IFNg and granzyme B.
Crucially, the anti-tumor effect was lost in mice lacking MAIT cells, showing they are essential for the anti-tumor effects. (4/10)

Oral AcAc is rarely studied, partly because it’s so unstable.
We solved this by giving esterified AcAc (EAA) in drinking water, which increased AcAc levels. Strikingly, EAA reduced tumor burden in multiple colorectal cancer models. (3/10)

Ketogenic diets have gotten attention for potential benefits in cancer, but their high fat content and carb restriction have undesirable effects.
Exogenous ketones are a more targeted approach, but their therapeutic potential isn’t clear. (2/10)

Acetoacetate suppresses colon cancer via an MR1-MAIT axis Colorectal cancer (CRC) is a leading cause of cancer mortality and additional preventative, and therapeutic strategies are urgently needed. Ketogenic diets have mixed effects on tumorigenesis and comp...

Excited to share a preprint from my postdoc @theGarrettLab- now on bioRxiv!
Oral acetoacetate (AcAc) suppresses tumor growth by expanding and activating MAIT cells… and the mechanism was a surprise 🧵👇 (1/10)
www.biorxiv.org/content/10.1...