iiinova — where your digital self keeps evolving

Nick DeVito @ndevitomd.bsky.social · 12/05/2026

Spectacular talk on young onset colorectal cancer by Kimmie Ng from @danafarber.bsky.social

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Nick DeVito @ndevitomd.bsky.social · 14/03/2026

Crush CRC is about to start!!! What a turnout on a beautiful day!

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Nick DeVito @ndevitomd.bsky.social · 12/01/2026

In summary: If we don't look, we don't know! we cover the immunotherapy compromising effects of corticosteroids and acetaminophen, and potentially beneficial effects of SSRIs, statins, GLP1 agonists, anti-histamines, and PCSK9 inhibitors. We can study this in many settings to modify management!

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Nick DeVito @ndevitomd.bsky.social · 15/12/2025

At the colorectal cancer alliance summit, where the goal is very, very clear:

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Nick DeVito @ndevitomd.bsky.social · 30/11/2025

Save the date: Saturday, March 14th, 2026 join us for the CRUSH Colorectal Cancer 5K at The River Church in Durham. Support our patients, advocates/caregivers, researchers, and community at this incredible event - You will not want to miss our speakers!

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Nick DeVito @ndevitomd.bsky.social · 26/08/2025

“Patriotism is not enough. I must have no hatred or bitterness for anyone.” A dose of wisdom from Edith Dawn over a hundred years ago #London

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Nick DeVito @ndevitomd.bsky.social · 23/07/2025

Ozzy! You will be missed, one of rock’s icons.

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Nick DeVito @ndevitomd.bsky.social · 22/06/2025

Since we all probably need some palate cleansers in our timelines today, here are some carnivorous plant photos from Wilmington NC- venus fly traps only grow within 100 miles of here, no where else in the world!

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Nick DeVito @ndevitomd.bsky.social · 11/06/2025

I am so honored by this teaching award, glad the new tumor immunology lecture has made such an impact - thank you Duke fellows!!

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Nick DeVito @ndevitomd.bsky.social · 08/06/2025

I wrote this on the board in our inpatient oncology work room last November and it has stayed up since, so I thought I would share:

“The healthiest trauma response is taking agency”

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Nick DeVito @ndevitomd.bsky.social · 01/06/2025

Lots of expensive booths with upscale lounges, virtual reality, robots, big screens, and of course lots of branded giveaways… In my 10+ years of going to #ASCO25 and this is the only one I have been impressed by. We get to make gift bags for kids at @luriecancer.bsky.social!!! Thats doing it right.

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Nick DeVito @ndevitomd.bsky.social · 01/06/2025

1. EC+FOLFOX is standard of care in 1L Braf mut CRC 2. Don’t fear the Ipi in Msi-h! Minimal toxicity increase but more CURES with Ipi combo over aPd1 monotherapy 3. Kras g12c is moving up and will likely achieve approvals in the near future 4. Stg 4 MSS CRC patients - sequence tumors at dx always!

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Nick DeVito @ndevitomd.bsky.social · 03/05/2025

We didn’t get the cover art but here is my evil lil AI generated hedgehog warding off good immune cells in favor of suppressive ones. #Gli2

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Nick DeVito @ndevitomd.bsky.social · 30/03/2025

The best Sunday mornings are homemade biscuit Sunday mornings #docswhocook

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Nick DeVito @ndevitomd.bsky.social · 22/03/2025

The CRUSH CRC 5k was such a fantastic event!! Thanks to everyone who participated! See you next year

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Nick DeVito @ndevitomd.bsky.social · 02/03/2025

Nbd just trying to resubmit a career defining K08 over here..

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Nick DeVito @ndevitomd.bsky.social · 25/02/2025

“Oversimplifying macrophage heterogeneity to M1/M2 is dangerous to our progress in immunotherapy” Paraphrasing Dr. Ginhoux here, couldn’t agree more particularly in the era of single cell technologies.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

I’ll wrap this up by saying that I am a first-gen doctor and scientist, raised by a single mom with little family support, and my career nor this work would not exist without the support from NIH-funded laboratories. Federally funding biomedical research makes American Dreams happen.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

This work was supported by the Damon Runyon Cancer Foundation, Conquer Cancer Foundation, valuable collaborators and priceless patient participation. It was conducted in an NIH/NCI funded laboratory.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

In sum, we define the Hedgehog transcription factor Gli2 as a hub of tumor immune evasion through Wnt ligand signaling and Prostaglandin E2 production.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

We hope to use our Gli2 (hedgehog/EMT/Wnt/Prostaglandin) signatures as a biomarker to select patients with melanoma, colon cancer, and other malignancies and identify who may benefit from selective prostaglandin receptor inhibition and/or Wnt ligand inhibition

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Coming full circle back to the clinic, we applied our Gli2 signature developed from the murine cell lines to an internal dataset and two external datasets. This shows a clear association of Gli2 activation and a lack of benefit from immunotherapy.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Remember, Gli2 is activated in this model after escape too. Here, we found that again Wnt ligand inhibition improves response after anti-PD-1 escape, but EP2/EP4 inhibition enhanced anti-PD-1 response only PRIOR to escape.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

We began using the autochthonous BRAF/PTEN melanoma model (genetically induced melanoma rather than implanted cells), which we have shown to resist anti-PD-1 and respond to Wnt ligand inhibition after immunotherapy escape.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Enough mechanism! Lets. Kill. Some. Tumors. TPST-1495 exhibited substantial monotherapy only in Gli2 active melanoma lines, and sensitized them to anti-PD-1 blockade. Even more effective with PORCN inhibition. Set difficulty to hard mode!

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

This is under further investigation, given the importance of these cells in immunotherapy resistance (inversely related to response and CXCL9 expression) and in liver metastasis, where Spp1 macs sequester and suppress CD8 T cells. pubmed.ncbi.nlm.nih.gov/37535729/ aacrjournals.org/cancerdiscov...

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Briefly, there are so many macrophages and M1/M2 is an incredibly insufficient classification system, I came to appreciate this when analyzing scRNAseq data. Here, our main finding was a reduction in Spp1+ macrophages with Wnt ligand inhibition.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

HOWEVER! TPST-1495 uniquely reduced cDC2 and mregDC populations and PORCN inhibition enhanced cDC2 phenotype, implying complementary, separate affects on the DC compartment via Wnt and prostaglandin signaling..

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

The DC differences were fascinating. Wnt ligand inhibition increased cDC1 numbers and function in tumors consistent with our previous work and the work of others, while EP2/EP4 inhibition only promoted a more T cell-favorable phenotype.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

TPST-1495 did partly restore the early effector CD8+ T cell population in Gli2 active tumors, which could be due to a direct effect of the selective prostaglandin receptor inhibitor, or due to the upregulation of the T cell recruiting chemokine, CXCL9, in cDC1s.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Interestingly in this study we observed a higher number of Tcf7+ memory progenitor CD8+ T cells with PORCN inhibition, while Tox hi, terminally exhausted CD8 T cells were reduced.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Wnt ligand inhibition did lead to higher expression of Klrg1 and Gzma in NK cells, which could be due to suppression of PMN-MDSC recruitment. We have previously shown PORCN inhibition to enhance CD8 T cell recruitment, as well.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Exploring the role of PGE2 further, we found that selective EP2/EP4 blockade relieved apoptosis of NK cells induced by Gli2 active tumors, as well as enhanced their function.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

We confirmed that TPST-1495 induced apoptosis in MDSCs. This convergence of immune suppressive pathways to support a specific cell type again highlights the importance of PMN-MDSCs in Gli2 active tumors.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Both inhibitors decreased MDSCs – differently. Where as Wnt signaling induces their recruitment, EP2/EP4 signaling via PGE2 prolongs their survival and enhances their suppressive function.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Or a selective prostaglandin receptor inhibitor (EP2/EP4, which are immune suppressive, while EP1/3 are spared and are immune stimulatory) TPST-1495, which is in trials, and performed single cell RNAseq on CD45+ cells from these tumors.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Now we needed to distinguish the immune effects of Wnt and Prostaglandins via Gli2. We took a control, the Gli2 CA line, and treated the latter with either the PORCN inhibitor which ablates all Wnt ligand secretion or..

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

We then demonstrated that Gli2-mediated MDSC recruitment dependent on the previously described Wnt5a-Yap-CXCL5 axis. Wnt5a genetic silencing also suppressed tumor growth and recruitment of MDSCs in vivo.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

MDSCs seem pretty important to you, Gli2! It would be a shame if someone…depleted them! Ahem, so, we depleted them with anti-Ly6G, and Gli2 lost immune evasive control completely, growing similar to control lines.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Activating Gli2 in a murine colorectal cancer model also led to similar Cox2 and Wnt5a upregulation. In vivo, subcutanous implantation of this line similarly altered the immune microenvironment, excluding CD8 T cells while enriched in MDSCs.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Similar relationships were seen in human melanoma and colon cancer cells, and we see a strong relationship between our Gli2 signature and a predetermined signature of prostaglandin signaling in the TCGA

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

We again found the inverse to be true, genetic knockout or Gant61 suppresses COX2. We showed that Ptgs2 is directly regulated by Gli2 using ChIP-qPCR in both the active and KO lines.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

sequence your cell lines! Here where we found Ptgs2 along with the prostaglandin transporter Slco2a1 amongst the most upregulated genes with Gli2 activation. We confirmed this with my favorite Western blot ever. PGE2 was also up by ELISA

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

In our bulk tumor RNAseq data, we noted an upregulation of Ptgs2, which encodes COX2, the primary enzyme synthesizing prostaglandin E2. I had thought this was due to the influx of Ptgs2 producing MDSCs into Gli2 active tumors, but it was the cancer cells themselves!

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Sorted CD11c+ DCs from Gli2 active tumors, revealed a marked reduction in cDC1-related genes – indicating DCs were directly suppressed by Gli2. This, as well as the lack of NK cells, made us think there was more that Gli2 was doing beyond the Wnt pathway…

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

Seeing decrease in antigen presenting, CD103+ DCs, we asked the question if this was due to a direct suppression or a lack of DC-recruiting chemokine production from NK cells. NK cells WERE suppressed, DC-recruiting chemokines were not. Total DCs unaffected.

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Nick DeVito @ndevitomd.bsky.social · 24/02/2025

We then tried to treat the Gli2 active model with anti-PD-1 which had a substantial blunted responses compared to controls, further confirming that we are recapitulating the EMT-related immunotherapy resistant state in melanoma

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