Interested in host-microbe interactions and how we can apply findings to develop immunotherapies? The come join us for an exciting workshop in October @cruk-si.bsky.social
www.crukscotlandinstitute.ac.uk/events/125-s...

And we did make it! Amazing day! We’re so grateful to all the friends, family and colleagues who helped us reach our fundraising goal!

Extremely hot #BigHike

We’re off on the #BigHike! Beautiful day for it, raising money for @cancerresearchuk.org
fundraise.cancerresearchuk.org/page/kendles...

Happy big birthday @roscobacterium.bsky.social ! Celebrated in style at lab meeting with Tiramisu made by @celespin.bsky.social 😋

And this mechanism also fits for E.coli. EV5 shows E. coli Nissle, another popular probiotic and BCT vector also causes aborted T cell activation - so caution I guess if you wanna couple this with checkpoint blockade (as there are no checkpoints to block if T cells are disabled). 11/12

Before you go - a couple of fun side notes from the sup figures. FIRST, we could have missed this phenotype without the Timer system, EV1 shows comparison with the Nr4a1-GFP and Nr4a1-Timer. GFP gives the impression all is fine bc it sticks around-don't get the info of seeing it turned off. 10/12

What about back in vivo, can it still work? Well the Asnase-deficient STm still controls tumour growth, despite losing some effect on tumour stemness. SO, bringing T cells back on board is a good thing. That's where this story ends, for now! Much to unpick still! 9/12

...not quite. Would have been a neat bundle of joy as is, but then we wondered about the effect on the tumour cell...so we looked and yup, Asn depletion is also reducing tumour c-myc...but that's a good thing! Use of the Asnase-KO STm restores tumour c-Myc and 'stemness' 8/12

What's going on? TCR signal transduction is fine...mTOR/AKT are fine. Finally (took us a while!) we found c-myc was the culprit - T cells in presence of STm TCM could not upreg protein levels required for metabolic switch, so activation aborts....cool....but why? 6/12

Turn to RNAseq and by 16hrs stim CD4's have failed metabolic reprogramming -> check functionally by seahorse - yep T cells can't upreg glycolysis, oxphos also impaired. This occurs even with just the conditioned medium of STm-infected org's, so it's soluble 5/12

T cells are dysfunctional. IFNy doesn't correlate with TCR activity, ↓PD-1 & ↓ polyfunctionality. Tumour organoid--T cell co-culture shows arrested TCR signalling after 24-48 hrs aCD3/CD28 stim. What is going on? 4/12

We used TCR reporter mice (Nr4a3-Timer) crossed with IFNy and induced colonic tumours with AOM/DSS (previous pub Mackie, JCI Insight shows efficacy of attenuated STm in this model). Like others we see ↑CD4 and CD8 infiltration and ↑IFNy...BUT...3/12