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THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells.
Sun, Chuang; Shou, Peishun; Du, Hongwei; Hirabayashi, Koichi; Chen, Yuhui; Herring, Laura E; Ahn, Sarah; Xu, Yang; Suzuki, Kyogo; Li, Guangming; Tsahouridis, Ourania; Su, Lishan; Savoldo, Barbara; Dotti, Gianpietro.
Afiliação
  • Sun C; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Shou P; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Du H; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Hirabayashi K; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Chen Y; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Herring LE; Michael Hooker Proteomics Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Ahn S; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Xu Y; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Suzuki K; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Li G; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Tsahouridis O; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Su L; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Savoldo B; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill,
  • Dotti G; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: gdotti@med.unc.edu.
Cancer Cell ; 37(2): 216-225.e6, 2020 02 10.
Article em En | MEDLINE | ID: mdl-32004441
ABSTRACT
Chimeric antigen receptor (CAR) T cell costimulation mediated by CD28 and 4-1BB is essential for CAR-T cell-induced tumor regression. However, CD28 and 4-1BB differentially modulate kinetics, metabolism and persistence of CAR-T cells, and the mechanisms governing these differences are not fully understood. We found that LCK recruited into the synapse of CD28-encoding CAR by co-receptors causes antigen-independent CAR-CD3ζ phosphorylation and increased antigen-dependent T cell activation. In contrast, the synapse formed by 4-1BB-encoding CAR recruits the THEMIS-SHP1 phosphatase complex that attenuates CAR-CD3ζ phosphorylation. We further demonstrated that the CAR synapse can be engineered to recruit either LCK to enhance the kinetics of tumor killing of 4-1BB CAR-T cells or SHP1 to tune down cytokine release of CD28 CAR-T cells.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos e Proteínas de Sinalização Intercelular / Peptídeos e Proteínas de Sinalização Intracelular / Proteína Tirosina Fosfatase não Receptora Tipo 6 / Receptores de Antígenos Quiméricos Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos e Proteínas de Sinalização Intercelular / Peptídeos e Proteínas de Sinalização Intracelular / Proteína Tirosina Fosfatase não Receptora Tipo 6 / Receptores de Antígenos Quiméricos Idioma: En Ano de publicação: 2020 Tipo de documento: Article