Hind Rafei
@hindrafei.bsky.social
Physician-scientist at MD Anderson Cancer Center investigating cellular immunotherapy for solid cancers with a focus on the solid TME. Opinions are my own.
Let us keep the collaboration going 💪🏻😊
June 10, 2025 at 3:03 AM
Let us keep the collaboration going 💪🏻😊
Thank you Merve! It was our honor and privilege to have you on the team 😊
June 10, 2025 at 2:56 AM
Thank you Merve! It was our honor and privilege to have you on the team 😊
Thank you Abhinav @abhinavjain-phd.bsky.social for your generous collaboration! Onto the next one together :)
June 6, 2025 at 3:18 AM
Thank you Abhinav @abhinavjain-phd.bsky.social for your generous collaboration! Onto the next one together :)
🧵20/
Let’s build the future of immunotherapy—together. 💥🧬
📬 Always open to ideas, collaborations, and conversations. Please reach out!
Let’s build the future of immunotherapy—together. 💥🧬
📬 Always open to ideas, collaborations, and conversations. Please reach out!
June 5, 2025 at 3:03 AM
🧵20/
Let’s build the future of immunotherapy—together. 💥🧬
📬 Always open to ideas, collaborations, and conversations. Please reach out!
Let’s build the future of immunotherapy—together. 💥🧬
📬 Always open to ideas, collaborations, and conversations. Please reach out!
🧵19/
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.
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.
June 5, 2025 at 3:03 AM
🧵19/
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.
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.
🧵18/
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.
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.
June 5, 2025 at 3:03 AM
🧵18/
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.
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.
🧵17/
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😅.
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😅.
June 5, 2025 at 3:03 AM
🧵17/
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😅.
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😅.
🧵16/
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.
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.
June 5, 2025 at 3:03 AM
🧵16/
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.
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.
🧵15/
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🙏🏻.
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🙏🏻.
June 5, 2025 at 3:03 AM
🧵15/
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🙏🏻.
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🙏🏻.
🧵14/
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🙏🏻.
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🙏🏻.
June 5, 2025 at 3:03 AM
🧵14/
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🙏🏻.
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🙏🏻.
🧵13/
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💉.
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💉.
June 5, 2025 at 3:03 AM
🧵13/
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💉.
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💉.
🧵12/
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.
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.
June 5, 2025 at 3:03 AM
🧵12/
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.
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.
🧵11/
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
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
June 5, 2025 at 3:03 AM
🧵11/
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
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
🧵10/
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
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
June 5, 2025 at 3:03 AM
🧵10/
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
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
🧵9/
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.
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.
June 5, 2025 at 3:03 AM
🧵9/
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.
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.
🧵8/
Functionally, CREM knockout (KO) in 2 different CAR models significantly enhanced cytotoxicity in 2D, 3D, and rechallenge assays. See👀for yourself:
Functionally, CREM knockout (KO) in 2 different CAR models significantly enhanced cytotoxicity in 2D, 3D, and rechallenge assays. See👀for yourself:
June 5, 2025 at 3:03 AM
🧵8/
Functionally, CREM knockout (KO) in 2 different CAR models significantly enhanced cytotoxicity in 2D, 3D, and rechallenge assays. See👀for yourself:
Functionally, CREM knockout (KO) in 2 different CAR models significantly enhanced cytotoxicity in 2D, 3D, and rechallenge assays. See👀for yourself:
🧵7/
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.
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.
June 5, 2025 at 3:03 AM
🧵7/
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.
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.
🧵6/
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.
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.
June 5, 2025 at 3:03 AM
🧵6/
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.
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.
🧵5/
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.
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.
June 5, 2025 at 3:03 AM
🧵5/
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.
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.
🧵4/
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
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
June 5, 2025 at 3:03 AM
🧵4/
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
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
🧵3/
How is CREM induced?
We demonstrate that both CAR CD3ζ ITAM signaling (lost when⚡️to CD3ζ.Y6F) and IL-15 can independently ⬆️CREM.
How is CREM induced?
We demonstrate that both CAR CD3ζ ITAM signaling (lost when⚡️to CD3ζ.Y6F) and IL-15 can independently ⬆️CREM.
June 5, 2025 at 3:03 AM
🧵3/
How is CREM induced?
We demonstrate that both CAR CD3ζ ITAM signaling (lost when⚡️to CD3ζ.Y6F) and IL-15 can independently ⬆️CREM.
How is CREM induced?
We demonstrate that both CAR CD3ζ ITAM signaling (lost when⚡️to CD3ζ.Y6F) and IL-15 can independently ⬆️CREM.
🧵2/
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.
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.
June 5, 2025 at 3:03 AM
🧵2/
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.
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.