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Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens.
McCutcheon, Sean R; Swartz, Adam M; Brown, Michael C; Barrera, Alejandro; McRoberts Amador, Christian; Siklenka, Keith; Humayun, Lucas; Ter Weele, Maria A; Isaacs, James M; Reddy, Timothy E; Allen, Andrew S; Nair, Smita K; Antonia, Scott J; Gersbach, Charles A.
Afiliación
  • McCutcheon SR; Department of Biomedical Engineering, Duke University, Durham, NC, USA.
  • Swartz AM; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
  • Brown MC; Department of Surgery, Duke University Medical Center, Durham, NC, USA.
  • Barrera A; Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
  • McRoberts Amador C; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
  • Siklenka K; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
  • Humayun L; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
  • Ter Weele MA; Department of Pharmacology and Cancer Biology, Durham, NC, USA.
  • Isaacs JM; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
  • Reddy TE; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
  • Allen AS; Department of Biomedical Engineering, Duke University, Durham, NC, USA.
  • Nair SK; Department of Biomedical Engineering, Duke University, Durham, NC, USA.
  • Antonia SJ; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
  • Gersbach CA; Duke Cancer Institute Center for Cancer Immunotherapy, Duke University School of Medicine, Durham, NC, USA.
Nat Genet ; 55(12): 2211-2223, 2023 Dec.
Article en En | MEDLINE | ID: mdl-37945901
Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas / Neoplasias Límite: Humans Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas / Neoplasias Límite: Humans Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos