Delgoffe Lab

ATTN Pennsylvania researchers: Sen. Fetterman is compiling a list of federal grants and loans across Pennsylvania that are impacted or potentially impacted. Please fill out his form and let him know! forms.office.com/pages/respon...

Sounds ominous.

Imagine if @aoc @sanders.senate.gov , every dem, SIMULTANEOUSLY held Town Halls where they allowed grant and contract recipients to explain to the country what it is they do and why it's important

Invite all media. Including RW podcasters. @spaces Flood the zone

Call it a Day Of Transparency

Only on twitter and late on Friday night and with plain English? Even the NOT reads like typical Musk tripe.

Goes without saying for scientists:

This means Musk and his kids have access to grant applications, study section reports, internal scoring, RPPRs. The core of the best ideas in US science. Will they steal those ideas?

#scicomm #neuroskyence #evodevo #publichealth 🧪🧑‍🔬

Are you interested in a postdoc with our group studying cancer immunometabolism? If you’re at #KSTcells25 @keystonesymposia.bsky.social DM me and let’s chat!

Thrilled to be flying in to Vancouver to kick off our @keystonesymposia.bsky.social meeting on T cell differentiation in tissues! Excited to be meeting up with friends old and new and share some work tomorrow on how metabolites in tumor tissue can directly induce immune dysfunction! #KSTCells25

Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which scratching exacerbates inflammation and wheth...

Why scratching makes a rash worse and a potential benefit to scratching--it reduced S. aureus on skin. Andrew Liu's paper from our lab is out now at #science #neuroimmune #immunology www.science.org/doi/10.1126/...

Attending @keystonesymposia.bsky.social joint meetings on Innate Immune Memory and T Cell Differentiation? Meet our Senior Scientific Editor Montse Cols @montse-jexpmed.bsky.social to discuss your research and ask any questions related to publication!

See our collection 👉 https://buff.ly/3CgbKL7

I think that’s part of it! We make cells under ludicrously hypermetabolic conditions. It’s like training at sea level and then expecting to perform at altitude!

Nourishing T Cells to Fight Cancer - UPMC & Pitt Health Sciences News Blog Researchers from the University of Pittsburgh have developed a new… Read more

inside.upmc.com/nourishing-t...

Thanks to my incredible team and funding through the Mark Foundation, @cancerresearchinst.bsky.social, @niaidnews.bsky.social, @upmchillmancc.bsky.social and the Hillman Cancer Center. Trials of ACT with DCA conditioning are on the horizon! 13/13

Blocking the citrate carrier with benzyl-trycarboxylate completely negated the beneficial effects of DCA on T cells, suggesting a large part of metabolic reprogramming with DCA was diverting glucose-derived carbon not just to mitochondria, but also to nuclear sources for epigenetic remodeling 12/

Finally, we asked HOW mitochondrial reprogramming as altering the T cell epigenome. Carbon doesn’t always get oxidized in the mitochondria: much of it can leave as citrate through the citrate carrier (Slc25a1) where it fuels the nucleocytoplasmic pool of acetyl-CoA. 11/

Metabolomic, epigenetic, and transcriptional analyses revealed DCA induces some metabolic rewiring that allows T cells to more metabolize physiologic carbon sources present in the serum. DCA conditioning also induces changes of the epigenome, especially around stemness genes like Tcf7 and Klf2. 10/

However, cotransfer experiments of control of DCA-conditioned T cells revealed an incredible QUANTITATIVE advantage of the DCA-conditioned T cells, evident acutely after infusion (3-6 h) and did not require even antigen to be present 9/

What was really intriguing is that when we looked at the ‘per cell’ functionality of the therapeutic T cells in vivo (after infusion) there were no appreciable differences. They differentiated into effector T cells and eventually became exhausted. 8/

So, we made therapeutic murine (Pmel) or human (CD19 CAR) T cells in the presence of DCA. When used to treat tumor-bearing mice, T cells cultured in DCA were dramatically more efficacious. This occurred in the absence of lymphodepletion, in vivo vaccination, or IL-2 treatments. 7/

Targeting PDHK1 with dichloroacetate (DCA) doesn’t starve the cell of glucose, it redirects pyruvate into the mitochondria. If we activated T cells normally and expanded them in DCA, they kinda looked like in vivo T cells! High mitochondrial capacity and only minor effects on T cell expansion! 6/

Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mit...

Back in 2018, we identified a signaling pathway originating at the TCR that triggered aerobic glycolysis: tyrosine phosphorylation of PDHK1, an inhibitory kinase for PDH. A kinase we could inhibit! pmc.ncbi.nlm.nih.gov/articles/PMC... 5/

This is not surprising – T cell mitogens trigger aerobic glycolysis. But even 7 days after expansion, these cells were still secreting lactate like whoa. So, the big questions was: could we target aerobic glycolysis in a smart way and get in vitro T cells to behave like long-lived in vivo ones? 4/

We first compared the same T cells (OT-I) expanded in vivo (Vaccinia-OVA) to those activated and cultured in vitro. Compared metabolically, VV-OVA-primed T cells, expanding at equivalent rates, had elevated mitochondrial capacity, while in vitro expanded T cells did A LOT more glycolysis. 3/

Cellular therapies all have a common thread: they need to spend time in vitro. But we all recognize that the in vitro environment is ridiculous hypermetabolic. So with the help of Andrew Frisch and Yiyang Wang in the lab, we asked a simple question: is hypermetabolic culture also a stressor? 2/

Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy T cell therapies for cancer currently rely on extensive in vitro expansion in hypermetabolic conditions. Frisch et al. demonstrate that T cells grown in vitro perform extensive aerobic glycolysis. Rer...

I'm delighted to share a new story from our lab published today at @cp-cellmetabolism.bsky.social! In it, we describe how cellular therapies for cancer can be metabolically and epigenetically enhanced by redirecting how glucose is utilized during in vitro expansion. 1/ www.cell.com/cell-metabol...

One week from now we’ll be deep into our conference on T cell differentiation in tissues! Look forward to seeing y’all in Vancouver! #KSTcells25 @keystonesymposia.bsky.social

PhD Dissertation and Final Examination announcement for PMI student Andrew Frisch entitled “In Vitro Modulation of T Cell Glucose Usage Improves In Vitro Function and Therapeutic Efficacy of Adoptive Cell Therapies for Cancer.”

Congratulations to PMI student Andrew Frisch from @delgoffelab.bsky.social on his upcoming thesis defense! Nice work, Andrew!