A5054892972- CAR-T cell therapy research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Single-cell and spatial transcriptomics
- Cancer Cells and Metastasis
- Immunotherapy and Immune Responses
- Virus-based gene therapy research
- Hippo pathway signaling and YAP/TAZ
- FOXO transcription factor regulation
- Digestive system and related health
- Cancer-related molecular mechanisms research
- PI3K/AKT/mTOR signaling in cancer
- Mechanisms of cancer metastasis
Dartmouth College
2020-2025
Dartmouth Hospital
2024
Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing assess role ~40 transcription factors (TFs) epigenetic modulators cell fate decisions. Unexpectedly, we found that knockout TF Klf2 resulted aberrant exhausted-like acute...
Abstract Chimeric-antigen receptor (CAR) T-cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR had little success solid tumors due to obstacles presented by the tumor microenvironment (TME) of these cancers. Here, we show that T cells armored with engineered IL-2 superkine Super2 and IL-33 were able promote control as a single-agent therapy. IFNγ perforin dispensable for effects Super2- IL-33-armored cells. synergized shift leukocyte proportions in TME recruit...
Abstract Akt kinases translate various external cues into intracellular signals that control cell survival, proliferation, metabolism and differentiation. This review discusses the requirement for its targets in determining fate function of T cells. We discuss importance at stages development including β-selection during which fulfills energy requirements highly proliferative DN3 also plays an integral role CD8 biology where regulation Foxo transcription factors mTORC1 metabolic activity...
Summary Generating balanced populations of CD8 effector and memory T cells is necessary for immediate durable immunity to infections cancer. Yet, a definitive understanding differentiation remains unclear. We used CARLIN, processive lineage recording mouse model with single-cell RNA-seq TCR-seq track endogenous antigen-specific during acute viral infection. identified diverse repertoire expanded T-cell clones represented by seven transcriptional states. TCR enrichment analysis revealed...
Abstract Foxo1 is an essential transcription factor required for the survival and differentiation of memory CD8 T cells, yet it unclear whether these Foxo1-dependent functions are inherently coupled. To address this question, we examined effects different posttranslational modifications. Phosphorylation by Akt kinases at three distinct residues well characterized to inhibit transcriptional activity. However, effect phosphorylation within its DNA-binding domain serine 209 Mst1 kinase not...
<div>Abstract<p>Chimeric-antigen receptor (CAR) T-cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR had little success solid tumors due to obstacles presented by the tumor microenvironment (TME) of these cancers. Here, we show that T cells armored with engineered IL-2 superkine Super2 and IL-33 were able promote control as a single-agent therapy. IFNγ perforin dispensable for effects Super2- IL-33-armored cells. synergized shift leukocyte proportions...
Supplementary Figure from Superkine IL-2 and IL-33 Armored CAR T Cells Reshape the Tumor Microenvironment Reduce Growth of Multiple Solid Tumors
<div>Abstract<p>Chimeric-antigen receptor (CAR) T-cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR had little success solid tumors due to obstacles presented by the tumor microenvironment (TME) of these cancers. Here, we show that T cells armored with engineered IL-2 superkine Super2 and IL-33 were able promote control as a single-agent therapy. IFNγ perforin dispensable for effects Super2- IL-33-armored cells. synergized shift leukocyte proportions...
Supplementary Figure from Superkine IL-2 and IL-33 Armored CAR T Cells Reshape the Tumor Microenvironment Reduce Growth of Multiple Solid Tumors
Abstract In response to viral infection, antigen specific naïve CD8 T cells expand give rise a heterogenous pool of effector consisting short-lived (SLECs) and memory precursor (MPECs). While these populations are phenotypically functionally well characterized, we still don’t fully understand how they arise from responsive cells. We have combined progressive lineage recording with single-cell RNA sequencing cell receptor delineate the early differentiation OVA-specific endogenous in acute...
Abstract Common lymphoid progenitors (CLPs) in the bone marrow give rise to both T and B cells, but mechanisms underpinning downstream cell fate decisions have yet be fully elucidated. We identified N-Myc Downstream Regulated Gene 3 (NDRG3) - a highly conserved regulator of Wnt/B-catenin signaling as novel lymphocyte substrate Akt kinase. To determine effect NDRG3 phosphorylation, hematopoietic stem cells (HSCs) overexpressing phospho-null (S331A) or phospho-mimetic (S331E) mutant were...
Generating balanced populations of CD8 effector and memory T cells is necessary for immediate durable immunity to infections cancer. Yet, a definitive understanding differentiation remains unclear. We used CARLIN, processive lineage recording mouse model with single-cell RNA-seq TCR-seq track endogenous antigen-specific during acute viral infection. identified diverse repertoire expanded T-cell clones represented by seven transcriptional states. TCR enrichment analysis revealed differential...
Abstract Foxo1 is an essential transcription factor required for the differentiation and survival of memory CD8 T cells. activity heavily regulated by post translational modifications, yet it unclear whether cell in same manner as survival. Two S/T kinases, Akt1 Mst1 phosphorylate Foxo1. While mediated phosphorylation known to inhibit transcriptional activity, effect remains poorly understood. To determine impact regulation on Foxo1-dependent survival, we generated variants that mimic...
Abstract B cells are a rare subset in the thymus, an environment that supports T cell development and inhibits commitment to other immune lineages. Yet thymic play important role negative selection of autoreactive cells. The origin from either committed or early thymocyte progenitors remains uncertain. We hypothesize progenitor heterogenous population can give rise both In our study we combined CRISPR/Cas9-dependent lineage recorder GESTALT with single RNAseq capture type information follow...