Hind Rafei

MD Anderson announces 10th cohort of Andrew Sabin Family Fellows The University of Texas MD Anderson Cancer Center today announced its 10th cohort of Andrew Sabin Family Fellows, comprised of 10 early career cancer researchers. Created to provide a dedicated source of funding for emerging clinician and scientist leaders, the Sabin Family Fellowship supports groundbreaking research that fuels MD Anderson’s mission to end cancer.

Congratulations to the 2025 Sabin Family Fellowship recipients, 10 early career researchers recognized for their bold, high-impact cancer research.

Thank you to the Sabin Family Fellowship for supporting the next generation of innovators. http://spr.ly/633254IbgR #EndCancer

Don't miss this killer episode!

Dr. Rizwan Romee talks about #NaturalKiller cells and how they can be engineered to target cancers.

Check it out: bit.ly/3I19hq6

Let us keep the collaboration going 💪🏻😊

Thank you Merve! It was our honor and privilege to have you on the team 😊

CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells - Nature The transcription factor CREM is a pivotal regulator of NK cell function, making CREM a valuable target to increase the efficacy of anticancer immunotherapies based on this cell population and chimeric antigen receptors.

Nature research paper: CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells

https://go.nature.com/4mNx4tJ

Thank you Abhinav @abhinavjain-phd.bsky.social for your generous collaboration! Onto the next one together :)

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Let’s build the future of immunotherapy—together. 💥🧬
📬 Always open to ideas, collaborations, and conversations. Please reach out!

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Finally, as I begin my independent career, I carry forward the questions, the grit, and the belief that immune cells can be reprogrammed to do more.

My research will focus on engineering next-gen CAR-T cells to overcome exhaustion in solid tumors.

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It took years of perseverance, countless sleepless nights in the lab, and relentless hard work to get here.
At one point, it truly felt like the whole world revolved around CREM.

Lesson? Trust your ideas. Ask the hard questions. And even when it’s tough—don’t give up.

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True story: the Nature revisions arrived the same day my son, Adam Karim (yes, a play on CREM!😜) was born via emergency C-section.

So yes, this paper was built on blood, sweat, and tears—and a little baby joy too🧬🍼💥. On the bright side, it’s easy to remember when the revisions were due😅.

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Deeply grateful to MD Anderson Cancer Center
@mdanderson.bsky.social a place where bold science meets a mission that matters 🎯.

And above all, thank you to the patients and their families who inspire us every day—your courage motivates everything we do.

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A huge THANK YOU to the @natureportfolio.nature.com
editorial team—our editor Dr. Zoltan Fehervari, and to our reviewers for their insightful, constructive feedback. Your guidance made this a stronger, sharper paper. We are truly grateful🙏🏻.

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This work wouldn’t have been possible without the incredible mentorship of Dr. Katy Rezvani, our lab members, our co-authors, and the generous support of our collaborators. Too many people to name, but each of you left a mark on this work—and on me.

Team science at its finest🙏🏻.

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In summary, we identify🔎CREM as a key🔑transcriptional checkpoint that limits CAR-NK cell function and persistence. CREM KO enhances cytotoxicity and in vivo efficacy across tumor models without added toxicity.

These findings highlight CREM as a targetable regulator to improve cell therapies💉.

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How does CREM restrain CAR-NK cell function? We used🔹ChIP-seq🔹RNA-seq🔹ATAC-seq to map CREM’s impact.

CREM rewires the NK cell epigenome, and its ❌ restores a metabolically fit🏃‍♀️, functionally potent💪🏻phenotype.

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In a metastatic CD70⁺ breast cancer PDX model, 🐁 treated with CREM KO CAR70/IL-15 NK cells showed:

✅ Significantly⬇️tumor burden
✅⬆️NK cell proliferation and tissue infiltration
✅🙅🏽‍♀️toxicity

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We next tested CREM KO CAR-NK cells in vivo across 3 models of hematologic and solid tumors. In an aggressive Raji lymphoma model, long-term cultured CREM KO cells:

✅Controlled tumor growth more effectively than WT
✅⬆️survival
✅⬆️proliferation & tissue infiltration

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We further show that:

✅ Effects were strongest💪🏽when both CAR and IL-15 signaling were active.
✅ Mutating⚡️CD3ζ ITAMs abrogated this effect.

Therefore, CREM is a potent intracellular checkpoint that limits CAR-NK efficacy.

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Functionally, CREM knockout (KO) in 2 different CAR models significantly enhanced cytotoxicity in 2D, 3D, and rechallenge assays. See👀for yourself:

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Mechanistically⚙️, we found that CREM is induced via the cAMP–PKA–CREB signaling cascade and is a direct transcriptional target of CREB, integrating↪️↩️signals from both CAR and cytokine activation.

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Is CREM relevant in the tumor microenvironment?

Across multiple scRNA-seq datasets, CREM was broadly enriched in tumor-infiltrating immune cells especially NK cells, T cells, and monocytes/macrophages.

It also correlated with poor prognosis in certain cancers from TCGA.

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Using CyTOF, when co-cultured with tumor, CREM-high NK cells were enriched in a cluster (red🔴) expressing both:

⬆️Activation markers (CD25, GZMB, NKp30, NKG2D)
⬆️Exhaustion/inhibitory receptors (TIGIT, LAG3, NKG2A)

☝🏼An immunophenotype of activation-induced exhaustion.

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CREM upregulation isn't unique to CARs. We found it’s broadly induced by NK cell activation, including by:

✨Cytokines: IL-2, IL-12, IL-18➡️moderate dose-dependent CREM induction
✨Receptor stimulation: CD16, NKp30, NKp46➡️ ITAM-driven CREM upregulation

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How is CREM induced?

We demonstrate that both CAR CD3ζ ITAM signaling (lost when⚡️to CD3ζ.Y6F) and IL-15 can independently ⬆️CREM.

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We used scRNA-seq on CD19-targeting, IL-15-secreting CAR-NK cells (CAR19/IL-15) before and after infusion into a Raji lymphoma 🐁 model.

CREM emerged as one of the top⬆️transcription factors after infusion.

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T cells have deservedly been in the🔦for cell therapy, but other engineered cell therapies are now📈. What mediates NK cell exhaustion remains an important unanswered❓.

CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells - Nature The transcription factor CREM is a pivotal regulator of NK cell function, making CREM a valuable target to increase the efficacy of anticancer immunotherapies based on this cell population and chimeri...

I’m thrilled to share our work out now in Nature identifying CREM as a central intracellular checkpoin in #CARNK cells.

📄Link: nature.com/articles/s41...

Our story👇🏼