iiinova — where your digital self keeps evolving

Ty Miller Lab @tymillerlab.bsky.social · 12/08/2025

Home cooked meals are the best. Grateful to have @vrishab_x's mother visit the lab from Seattle and cook us all authentic South Indian food for lunch today 😋❤️

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Ty Miller Lab @tymillerlab.bsky.social · 06/08/2025

Celebrating "UH100", the 100th brain tumor we've collected (in ~10 months!) & processed to learn more about these tumors & make patient organoids to test new therapies @uhreinstitute.bsky.social & @caseccc.bsky.social. Thanks to the patients, @staudtmd.bsky.social & Dr. Tiffany Hodges, & my lab!

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Ty Miller Lab @tymillerlab.bsky.social · 15/04/2025

Our lab @caseccc.bsky.social, CWRU SOM, & University Hospitals is recruiting! We are looking for 2 talented immunotherapy postdocs eager to make an impact for brain tumor patients using cutting edge single-cell & spatial genomics & patient-tissue organoids - join us! Please share positions below:

We have a fun, collaborative group that includes medical and graduate students, staff, residents/fellows, neurosurgeons, neuro-oncologists and neuro-pathologists. Picture from lab holiday party at my house with our close collaborators - Dr. Tiffany Hodges (leader of brain tumor neurosurgery at UH) and Dr. Herb Newton (head of neuro-oncology at UH).

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Ty Miller Lab @tymillerlab.bsky.social · 31/03/2025

Honored for our lab to be highlighted in the @caseccc.bsky.social annual report - I can't say enough great things about the environment and support for our new lab. 9 months in and so happy to be @CWRUSOM and @caseccc! A couple pictures in the lab that didn't make the report:

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Ty Miller Lab @tymillerlab.bsky.social · 22/03/2025

Celebrating two summer fellowships today with ice cream @ Mitchells! Congrats to Kaylie for being awarded the CanSUR fellowship for undergraduates and Medical student Alex Wang the @caseccc.bsky.social Medical Training Award! Both awards will support their work in the lab this summer 🔬

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Ty Miller Lab @tymillerlab.bsky.social · 14/03/2025

Was great to see friends and colleagues in London as part of the @braintumourcharity.bsky.social annual Scientific Advisory Board meeting! There are exciting things happening in brain tumor research around the world and honored to get to help guide it. Views were pretty good toon

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

In summary, we utilized a new analytical tool, cNMF, to define consensus myeloid programs in glioma & revealed 4 dominant immunomodulatory programs that were previously hidden. Being able to study them in isolation reveals their drivers and ways to target them.

Microglial Inflam.↔️low grade, only in brain
Systemic Inflam. = default inflam response, seen systemically and in all tumors
Scav. Supp.↔️hypoxia, IL1B, TGFB; only in brain tumors
Complement Supp. <-Dex, endogenous stress hormones; seen in all tumor types

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

The clusters in prior important studies of myeloid cells in glioma (which taught us a lot) end up being composites of our programs – with our cell identity programs being captured well by 1-3 clusters, but the activities programs being shared across many clusters.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Notably, we would not have been able to find these important programs and study them in isolation with a traditional clustering/UMAP strategy. Clustering is good for finding cell types, but not activities, which are shared across clusters.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Taking all this data together, and through many conversations with a lot of really smart people over the last 4+ years, we now think about myeloid cells in glioma through this framework (which is probably applicable to other solid tumors):

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

These 4 immunomodulatory programs dictate the overall immune state tumor and are very interconnected!

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Excitingly, we could reprogram the immunosuppressive macrophages back to their default inflammatory state using a p300 inhibitor from @genentech.bsky.social

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Using clinical data, we found the Complement Suppressive program is specifically & irreversibly driven by dexamethasone, a potent corticosteroid given to most patients for symptom & surgical management. High IFNg only partially rescued. Most IO trials in GBM allow some dex use...

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

We identified IL1B as a major driver of the Scavenger suppressive program, which is being produced by monocytes that enter the tumor expressing the System Inflammatory program. Likely an evolutionary feedback loop to reduce inflammation in the brain!

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Given their apparent importance, we dove in to discover the mechanisms underlying these immunosuppressive programs. We used snATAC-seq data to identify transcription factors at the heart of these programs and then identified upstream regulators of these TFs.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

It turns out that it was the Scavenger Suppressive program, not any cell type, that was associated with immunotherapy resistance, higher Tregs in tumors, and overall worse survival in patients – only discoverable because we can now study this program in isolation:

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

The authors found SIGLEC9 is a mediator of resistance. We plotted their cells according to our program usage & then labeled SIGLEC9+ cells. They were quite diverse in our program expression. However, responder/non-responder tumor cells almost perfectly segregated by our programs!

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Importantly, do these programs matter clinically? Fortunately, a paper was published this summer with a scRNA-seq dataset of 12 patients w/ neoadjuvant PD1 blockade, categorized as responder or non-responder.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Using a new spatial regression model by @CouturierMDPhD & @davidsebfischer.bsky.social, we aggregated the spatial association data of tumor niches & our cellular programs across sections. We created a spatial map from the data - each activity program had a distinct tumor niche.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Grade = microenvironment under a microscope, so we looked to see what specific environments in the tumor were associated w/specific myeloid activities using 10X Visium data from @milolab.bsky.social .Our Scavenger Suppressive program was only in hypoxia. The Complement Suppressive? Everywhere else

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

We also looked to see if IDH mutation was a driver of myeloid activity. While the Microglial inflammatory program was very enriched, and the 2 immunosuppressive programs were depleted, this turns out to be entirely driven by tumor GRADE not IDH mutation.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Side note, we found that myeloid cells were so plastic that even some cells expressing microglia programs were derived from circulating monocytes. We validated this ex vivo - when we applied peripheral monocytes to patient organoids, they infiltrate & express microglia markers!?

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

This made us rethink how we should view myeloid cells. Rather than taking a cell type-centric approach, we decided to focus on the immunomodulatory programs and study myeloid cells in that way (in a cell-type agnostic way). This plot becomes very useful to do that.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

And they were shared across myeloid cell types = the same activity program was being expressed in different microglia, macrophage, and monocytes.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Surprisingly, these 4 immunomodulatory were the most utilized programs across myeloid cells (d). Nearly all (91%) of myeloid cells in our gliomas expressed at least one of these 4 programs

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

There were 14 superimposable programs. 5 cell identity programs (defines cell type of cell), and 9 activity programs (what cell is doing). Notably, 4 of these activity programs seem immunomodulatory in their activity, with 2 inflammatory and 2 suppressive

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

I could go on for 20 tweets about how we got to these programs (it took 2 years to develop the strategy we felt captured the true consensus programs), but the key was utilizing cNMF (from @dkotliar.bsky.social @pardissabeti.bsky.social)rather than the standard Louvain clustering w/UMAP (see methods)

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

So that’s what we set out to do. While we knew about malignant cells in glioma from scRNA-seq studies & had some consensus in the field, that’s not the case for myeloid cells. So 1st, we set to create consensus myeloid programs across gliomas(which are diverse = need many tumors)

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

6 yrs ago, when I started residency @ MGH & joined Brad's lab, I asked a Q: “What’s our best shot at a cure for #glioma patients?” A: Immunotherapy. Q: “How do we make immunotherapy effective for glioma?” A: Start by tackling the immunosuppressive myeloid cells.

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Ty Miller Lab @tymillerlab.bsky.social · 27/02/2025

Quick tangent: we are recruiting postdocs! This work lays a foundation of discovery & translation that I’ve brought to my own lab @caseccc.bsky.social & CWRU SOM – where we have built a fun, collaborative, & intelligent team driven to make an impact. Join us! tymillerlab.org/our-team/

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Ty Miller Lab @tymillerlab.bsky.social · 23/02/2025

At #TRCCC @ejohnwherry.bsky.social gave an amazing talk about changing delivery of checkpoint blockade to increase efficacy, then ended with this slide, maybe his most important of the day. Share this information with your friends, family, neighbor!

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Ty Miller Lab @tymillerlab.bsky.social · 20/02/2025

Proud of my lab members who gave great talks today @ the #TRCCC conference!! Vrishab Kumar & Regan Murphy presented their computational projects this morning, and Shawn Ho & Alex Crane presented myeloid targeting projects this evening. CWRU SOM & @caseccc.bsky.social representing 💯

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Ty Miller Lab @tymillerlab.bsky.social · 19/02/2025

The @tymillerlab.bsky.social rolling into #TRCCC 2025 and looking forward to 3 great days learning about the latest in immunotherapy!! #Roadtrip

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Ty Miller Lab @tymillerlab.bsky.social · 11/12/2024

Excited to be at @UCSF & @UCSFCancer to give the @UcsfPspg seminar today about our work and meet with friends and colleagues! Thanks to @LuRongze for the invite!

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Ty Miller Lab @tymillerlab.bsky.social · 06/12/2024

The Miller Lab birthday tradition continues at Mitchell's - happy birthday Namita!

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Ty Miller Lab @tymillerlab.bsky.social · 09/11/2024

I'll say it again, the best part of #SITC2024 is the people @NeuroOncDoc @mwilli323 @SRamakrishna_MD @maraademartino and friends 😁 Thanks for hosting @AkoyaBio!

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Ty Miller Lab @tymillerlab.bsky.social · 07/11/2024

Excited to be at #SITC2024 - as faculty for the first time! 🤎 badge ribbons, which basically lay out my @sitcancer & @sitcancerECS journey 😀 Recruiting postdocs that are motivated to create effective immunotherapies for brain tumor patients! Reach out! Tymillerlab.org

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Ty Miller Lab @tymillerlab.bsky.social · 29/10/2024

Most importantly, I’m grateful to my incredibly supportive family – to get to this place in science/medicine is a long haul and no one gets here alone. My parents and my wife, who’s been by my side for 21 years, enabled me to pursue this dream position 💗🙏

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Ty Miller Lab @tymillerlab.bsky.social · 29/10/2024

I’ve been so fortunate to have great mentors throughout my career & blown away that many took time out to be at my ceremony. They taught me how to conduct, love, & flourish in science. Incl: Sarmila Majumder, Jeremy Rich, @TesarLab @BradEBernstein @MarioSuva Time to #PayItForward

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Ty Miller Lab @tymillerlab.bsky.social · 29/10/2024

I’m so excited to be back in Cleveland at my Alma Mater to lead a growing lab of motivated, intelligent, & fun colleagues. This endowment will provide continual, stable support for our work to create effective immunotherapies for brain tumor patients -> tymillerlab.org

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Ty Miller Lab @tymillerlab.bsky.social · 29/10/2024

I am honored and humbled to be appointed as the Paul and Betsy Shiverick Professor of Immuno-Oncology. I’m very grateful for generosity and the vision of Paul and Betsy to establish this Professorship &feel incredibly fortunate to be the inaugural chairholder @caseccc & @CWRUSOM!

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Ty Miller Lab @tymillerlab.bsky.social · 05/10/2024

Great to have @CouturierMDPhD visit the lab this week! Looking forward to many continued close collaborations, my friend!

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Ty Miller Lab @tymillerlab.bsky.social · 29/09/2024

Happy to support the @theABTA this morning in the first annual Cleveland BT5K! Thanks to my co-captain of the @caseccc team, @JustinLathia - proud to have @ClevelandClinic, @CWRUSOM, @UHhospitals researcher & docs team up! Cleveland is the place to be for #braintumor research!

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Ty Miller Lab @tymillerlab.bsky.social · 28/09/2024

The @TyMillerLab showed out this morning to support @theABTA as part of the @caseccc team! Love that the lab gets engaged supporting brain tumor research funding! Thanks @estrada__edward @Shawn_T_Ho @ReganMurphy20 @Vrishab_x & Meirola! #ClevelandBT5K

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Ty Miller Lab @tymillerlab.bsky.social · 28/09/2024

That's a wrap on #ReThinkNeuroimmunology 2024! Thanks to @IdoAmitLab and @jonykipnis for an incredible meeting with lots of thought-provoking presentations and conversations. Was honored to be able to present our work and ideas. Until next time!

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Ty Miller Lab @tymillerlab.bsky.social · 25/09/2024

Great to present our work on understanding and targeting immunosuppressive myeloid cells at #CRUKbrain2024 Also wonderful to get to catch-up with old and new friends! #braintumour

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