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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

If you’re interested in joining the lab, drop me an email. We’re working on some exciting things which will 🤞🏾hopefully🤞🏾 be supported by a DP2 soon.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

This work was led by @ScienceWansang (who will be on the faculty job market in coming years), Jenny Liu (starting grad school at UCSF this fall), and @AlexBeckettPhD (who is now at Kite).

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

This work was funded by @Hypothesisfund , Shurl and Kay Curci Foundation, @StanfordCancer , @parkerici , and others. Thank you to @stevenschem , @xrtcell, and the Stanford community for feedback.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

If you’d like to share constructive criticism or suggest important references, email kyledan@stanford.edu.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

We hope this work provides insights into how signaling motifs work together to set cell signaling and phenotype, and that those insights can lead to better, safer cell therapies. If you’re interested, please read our manuscript and share with anyone else who might be interested.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

Our map of the signaling-phenotype landscape suggests that a delicate balance between STATs determines CAR T cell function. There’s a continuous spectrum of STAT signaling, and it corresponds to a continuous shift in CAR T cell cytotoxicity and memory.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

We used these models to map the signaling-phenotype landscape, building a quantitative map of how STAT signaling encodes different CAR T cell phenotypes. Which combinations of STATs drive CAR T cells to functional states we might want to access?

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

To understand how signaling motifs in the SCR encode function, we trained models that use motif combination to predict killing, memory, proliferation, or cell signaling. These models help us pull out important information like which features cause unsafe proliferation.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

Some SCRs with synthetic signaling domains, like SCR 421, greatly improved tumor control in a mouse xenograft model.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

Over the course of a 9 day co-culture with target cancer cells, SCRs increased CAR T cell cytotoxicity and proliferation. At the end of the co-culture, when CAR control was overwhelmed with cancer cells, many SCRs maintained killing activity.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

Cytokine receptor signaling domains often contain several signaling motifs. We tested over 450 designs with shuffled motif combinations for their effects on CAR T cell functions: survival in the absence of cytokine, proliferation, differentiation, and killing. What did we find?

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

What are signaling motifs? They’re short stretches of amino acids that bind some of our favorite signaling proteins. For example, YLPQ motif from the IL9 receptor has a canonical YxxQ STAT-binding motif that activates txn factors STAT1 & 3 to turn on gene expression.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

We built a constiutively dimerized chimeric cytokine receptor platform that provides constant cell signaling without ligand. The cell signaling is determined by the signaling motifs we add. Each motif has a unique signaling pattern and effect on cell phenotype.

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

Cytokine signaling is critical for CAR T cell function. How do cytokine receptor signaling domains encode so many different immune cell phenotypes. To find out, we made hundreds of synthetic signaling domains and asked how they reshaped CAR T cell function. #synbio #CARTcell

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Kyle G Daniels @sciencekyle.bsky.social · 06/06/2025

🚨 New Preprint 🚨 A continuous landscape of signaling encodes a corresponding landscape of CAR T cell phenotype How can we tune JAK/STAT signaling to create better immune cell therapies? doi.org/10.1101/2025.0…

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