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Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.
Vardhana, Santosha A; Hwee, Madeline A; Berisa, Mirela; Wells, Daniel K; Yost, Kathryn E; King, Bryan; Smith, Melody; Herrera, Pamela S; Chang, Howard Y; Satpathy, Ansuman T; van den Brink, Marcel R M; Cross, Justin R; Thompson, Craig B.
Afiliação
  • Vardhana SA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Hwee MA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Berisa M; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
  • Wells DK; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Yost KE; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • King B; The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Smith M; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
  • Herrera PS; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
  • Chang HY; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Satpathy AT; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • van den Brink MRM; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Cross JR; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Thompson CB; Weill Cornell Medical College, New York, NY, USA.
Nat Immunol ; 21(9): 1022-1033, 2020 09.
Article em En | MEDLINE | ID: mdl-32661364
The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos do Interstício Tumoral / Linfócitos T CD8-Positivos / Mitocôndrias / Neoplasias Limite: Animals Idioma: En Revista: Nat Immunol Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos do Interstício Tumoral / Linfócitos T CD8-Positivos / Mitocôndrias / Neoplasias Limite: Animals Idioma: En Revista: Nat Immunol Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos