9 results on '"Ansuman T. Satpathy"'
Search Results
2. c-Jun overexpression in CAR T cells induces exhaustion resistance
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Robert C. Jones, Surya Nagaraja, Ansuman T. Satpathy, Michelle Monje, Zinaida Good, Elena Sotillo, Howard Y. Chang, Peng Xu, Hima Anbunathan, Evan W. Weber, Crystal L. Mackall, Rachel C. Lynn, Charles F. A. de Bourcy, David Gennert, John Lattin, Jeffrey M. Granja, Robbie G. Majzner, Victor Tieu, and Stephen R. Quake
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0301 basic medicine ,Transcription, Genetic ,Proto-Oncogene Proteins c-jun ,T cell ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Article ,Epigenesis, Genetic ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Antigen ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Receptor ,Transcription factor ,Multidisciplinary ,Chemistry ,c-jun ,Chimeric antigen receptor ,Cell biology ,Chromatin ,Transcription Factor AP-1 ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Cell culture ,030220 oncology & carcinogenesis ,human activities - Abstract
Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer1-3, but dysfunction due to T cell exhaustion is an important barrier to progress4-6. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion6. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells7-10. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.
- Published
- 2019
3. RASA2 ablation in T cells boosts antigen sensitivity and long-term function
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Julia Carnevale, Eric Shifrut, Nupura Kale, William A. Nyberg, Franziska Blaeschke, Yan Yi Chen, Zhongmei Li, Sagar P. Bapat, Morgan E. Diolaiti, Patrick O’Leary, Shane Vedova, Julia Belk, Bence Daniel, Theodore L. Roth, Stefanie Bachl, Alejandro Allo Anido, Brooke Prinzing, Jorge Ibañez-Vega, Shannon Lange, Dalia Haydar, Marie Luetke-Eversloh, Maelys Born-Bony, Bindu Hegde, Scott Kogan, Tobias Feuchtinger, Hideho Okada, Ansuman T. Satpathy, Kevin Shannon, Stephen Gottschalk, Justin Eyquem, Giedre Krenciute, Alan Ashworth, and Alexander Marson
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Time Factors ,General Science & Technology ,T-Lymphocytes ,Adoptive ,Receptors, Antigen, T-Cell ,Immunotherapy, Adoptive ,Mice ,Antigens, Neoplasm ,Bone Marrow ,Neoplasms ,Receptors ,Genetics ,2.1 Biological and endogenous factors ,Animals ,Humans ,Antigens ,Aetiology ,Cancer ,Multidisciplinary ,Leukemia ,Receptors, Chimeric Antigen ,5.2 Cellular and gene therapies ,Animal ,Prevention ,Chimeric Antigen ,T-Cell ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,5.1 Pharmaceuticals ,ras GTPase-Activating Proteins ,Antigen ,Gene Knockdown Techniques ,Disease Models ,Neoplasm ,Immunotherapy ,Development of treatments and therapeutic interventions ,CRISPR-Cas Systems ,Biotechnology - Abstract
The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3–10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.
- Published
- 2021
4. Publisher Correction: A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation
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Ranit Kedmi, Tariq A. Najar, Kailin R. Mesa, Allyssa Grayson, Lina Kroehling, Yuhan Hao, Stephanie Hao, Maria Pokrovskii, Mo Xu, Jhimmy Talbot, Jiaxi Wang, Joe Germino, Caleb A. Lareau, Ansuman T. Satpathy, Mark S. Anderson, Terri M. Laufer, Iannis Aifantis, Juliet M. Bartleson, Paul M. Allen, Helena Paidassi, James M. Gardner, Marlon Stoeckius, and Dan R. Littman
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Multidisciplinary - Published
- 2022
5. ecDNA hubs drive cooperative intermolecular oncogene expression
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Robert Schöpflin, Vineet Bafna, Liangqi Xie, Konstantin Helmsauer, M. Ryan Corces, Natasha E. Weiser, Zhe Liu, Anton G. Henssen, Anindya Bagchi, Howard Y. Chang, Utkrisht Rajkumar, Rui Li, Katerina Kraft, Kathryn E. Yost, Robert Tjian, Sihan Wu, Julia A. Belk, Jens Luebeck, Siavash R. Dehkordi, King L. Hung, Celine Chen, Paul S. Mischel, Ivy Tsz-Lo Wong, Jun Tang, Jordan Friedlein, Stefan Mundlos, Quanming Shi, Joshua T. Lange, Rocío Chamorro González, Connor V. Duffy, John C. Rose, M. E. Valieva, Jeffrey M. Granja, and Ansuman T. Satpathy
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Regulation of gene expression ,BRD4 ,CRISPR interference ,Multidisciplinary ,Gene Amplification ,Nuclear Proteins ,Cell Cycle Proteins ,Azepines ,Oncogenes ,Biology ,Cell biology ,Gene Expression Regulation, Neoplastic ,Cell Line, Tumor ,Neoplasms ,Transcriptional regulation ,Gene silencing ,Humans ,Cancer epigenetics ,Enhancer ,Gene ,Transcription Factors - Abstract
Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs—clusters of around 10–100 ecDNAs within the nucleus—enable intermolecular enhancer–gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer–gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy. Extrachromosomal DNA (ecDNA) congregates in clusters called ecDNA hubs that promote intermolecular interactions between gene-regulatory regions and thereby amplify the expression of oncogenes such as MYC in cancer cell lines.
- Published
- 2020
6. Author Correction: Discovery of stimulation-responsive immune enhancers with CRISPR activation
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Maxwell R. Mumbach, Nicki Naddaf, Theodore L. Roth, Nicolas Bray, Ruize Liu, Chun Jimmie Ye, K. Mark Ansel, Graham J. Ray, Mark S. Anderson, Dmytro Lituiev, Benjamin G. Gowen, Zhongmei Li, Therese Mitros, John D. Gagnon, Kyle Kai-How Farh, Hong Ma, Jacob E. Corn, Eric Boyer, Hailiang Huang, Youjin Lee, William J. Greenleaf, Rachel E. Gate, Victoria Tobin, Julia S. Chu, Meena Subramaniam, Ansuman T. Satpathy, Kathrin Schumann, Gemma L. Curie, Alexander Marson, Alice Y. Chan, Jonathan M. Woo, Mandy Boontanrart, Mark J. Daly, Michelle L.T. Nguyen, Frédéric Van Gool, Dimitre R. Simeonov, Howard Y. Chang, and Jeffrey A. Bluestone
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Genetics ,Multidisciplinary ,T cell ,Stimulation ,Single-nucleotide polymorphism ,Biology ,Phenotype ,Article ,Immune system ,medicine.anatomical_structure ,Genotype ,medicine ,SNP ,Enhancer - Abstract
The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues1–3. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption4–6, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa)7 to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.
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- 2018
7. MONDAY PUSHLIVE TEST L-Myc expression by dendritic cells is required for optimal T-cell priming
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Vivek Durai, Theresa L. Murphy, Marco Colonna, Emilie V. Russler-Germain, Barry P. Sleckman, Michel C. Nussenzweig, Ansuman T. Satpathy, Aaron S. Rapaport, Stephen P. Persaud, Jakob Loschko, Marina Cella, Kenneth M. Murphy, Jörn C. Albring, Nicole M. Kretzer, Paul M. Allen, Brian T. Edelson, Xiaodi Wu, Carlos G. Briseño, and Wumesh Kc
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Multidisciplinary ,medicine.anatomical_structure ,T cell ,medicine ,Priming (immunology) ,Biology ,Cell biology - Published
- 2014
8. L-Myc expression by dendritic cells is required for optimal T-cell priming
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Vivek Durai, Brian T. Edelson, Kenneth M. Murphy, Barry P. Sleckman, Carlos G. Briseño, Ansuman T. Satpathy, Marco Colonna, Marina Cella, Paul M. Allen, Jörn C. Albring, Wumesh Kc, Emilie V. Russler-Germain, Nicole M. Kretzer, Stephen P. Persaud, Michel C. Nussenzweig, Xiaodi Wu, Jakob Loschko, Theresa L. Murphy, and Aaron S. Rapaport
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Male ,Transcription, Genetic ,T cell ,T-Lymphocytes ,Priming (immunology) ,Article ,Proto-Oncogene Proteins c-myc ,Mice ,Immune system ,Cross-Priming ,Antigens, CD ,medicine ,Animals ,Transcription factor ,Lung ,Regulation of gene expression ,Inflammation ,Multidisciplinary ,biology ,Cell growth ,Granulocyte-Macrophage Colony-Stimulating Factor ,Dendritic Cells ,Vesiculovirus ,biology.organism_classification ,Listeria monocytogenes ,Cell biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Liver ,Vesicular stomatitis virus ,Immunology ,Interferon Regulatory Factors ,Female ,IRF8 ,Integrin alpha Chains ,Cell Division - Abstract
The transcription factors c-Myc and N-Myc--encoded by Myc and Mycn, respectively--regulate cellular growth and are required for embryonic development. A third paralogue, Mycl1, is dispensable for normal embryonic development but its biological function has remained unclear. To examine the in vivo function of Mycl1 in mice, we generated an inactivating Mycl1(gfp) allele that also reports Mycl1 expression. We find that Mycl1 is selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression is initiated in the common DC progenitor concurrent with reduction in c-Myc expression. Mature DCs lack expression of c-Myc and N-Myc but maintain L-Myc expression even in the presence of inflammatory signals such as granulocyte-macrophage colony-stimulating factor. All DC subsets develop in Mycl1-deficient mice, but some subsets such as migratory CD103(+) conventional DCs in the lung and liver are greatly reduced at steady state. Importantly, loss of L-Myc by DCs causes a significant decrease in in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming.
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- 2012
9. Compensatory dendritic cell development mediated by BATF-IRF interactions
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Robert D. Schreiber, Jörn C. Albring, Harinder Singh, Leslie A. Weiss, Cora T. Aurthur, Samuel S. K. Lam, Elke Glasmacher, Nicole M. Kretzer, Michael S. Behnke, Wei Liao, Theresa L. Murphy, Xiaodi Wu, Ansuman T. Satpathy, Mona Mashayekhi, Wan-Ling Lee, Peng Li, Kenneth M. Murphy, L. David Sibley, Christina L. Stallings, Wumesh Kc, Roxane Tussiwand, Jeffrey A. Rotondo, Warren J. Leonard, and Brian T. Edelson
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CD4-Positive T-Lymphocytes ,Male ,Cellular differentiation ,CD8 Antigens ,Fibrosarcoma ,Antigen presentation ,Oncogene Protein p65(gag-jun) ,Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Antigens, CD ,Cell Line, Tumor ,BATF ,Animals ,CTLA-4 Antigen ,Cell Lineage ,030304 developmental biology ,0303 health sciences ,Antigen Presentation ,Leucine Zippers ,Multidisciplinary ,Cell Differentiation ,Dendritic cell ,Dendritic Cells ,T-Lymphocytes, Helper-Inducer ,Interleukin-12 ,Cell biology ,Interleukin-10 ,Protein Structure, Tertiary ,Mice, Inbred C57BL ,Repressor Proteins ,Interleukin 10 ,AP-1 transcription factor ,Basic-Leucine Zipper Transcription Factors ,Gene Expression Regulation ,Immunology ,Interferon Regulatory Factors ,Interleukin 12 ,Female ,Integrin alpha Chains ,Toxoplasma ,Neoplasm Transplantation ,030215 immunology ,Interferon regulatory factors ,Protein Binding - Abstract
The AP1 transcription factor Batf3 is required for homeostatic development of CD8α(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8α(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.
- Published
- 2012
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