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PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance.
Verma, Vivek; Shrimali, Rajeev K; Ahmad, Shamim; Dai, Winjie; Wang, Hua; Lu, Sumin; Nandre, Rahul; Gaur, Pankaj; Lopez, Jose; Sade-Feldman, Moshe; Yizhak, Keren; Bjorgaard, Stacey L; Flaherty, Keith T; Wargo, Jennifer A; Boland, Genevieve M; Sullivan, Ryan J; Getz, Gad; Hammond, Scott A; Tan, Ming; Qi, Jingjing; Wong, Phillip; Merghoub, Taha; Wolchok, Jedd; Hacohen, Nir; Janik, John E; Mkrtichyan, Mikayel; Gupta, Seema; Khleif, Samir N.
Afiliação
  • Verma V; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
  • Shrimali RK; The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
  • Ahmad S; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
  • Dai W; Therapeutic Discovery, MD Anderson Cancer Center, Houston, TX, USA.
  • Wang H; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
  • Lu S; Five Prime Therapeutics Inc., South San Francisco, CA, USA.
  • Nandre R; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
  • Gaur P; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
  • Lopez J; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
  • Sade-Feldman M; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
  • Yizhak K; The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
  • Bjorgaard SL; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
  • Flaherty KT; The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
  • Wargo JA; The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
  • Boland GM; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • Sullivan RJ; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Getz G; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Hammond SA; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • Tan M; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Qi J; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • Wong P; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Merghoub T; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Wolchok J; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • Hacohen N; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • Janik JE; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Mkrtichyan M; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • Gupta S; MedImmune LLC, Gaithersburg, MD, USA.
  • Khleif SN; Department of Biostatistics, Bioinformatics & Biomathematics, Georgetown University, Washington, DC, USA.
Nat Immunol ; 20(9): 1231-1243, 2019 09.
Article em En | MEDLINE | ID: mdl-31358999
ABSTRACT
Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glicoproteínas de Membrana / Linfócitos T CD8-Positivos / Resistencia a Medicamentos Antineoplásicos / ADP-Ribosil Ciclase 1 / Receptor de Morte Celular Programada 1 / Neoplasias Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Nat Immunol Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glicoproteínas de Membrana / Linfócitos T CD8-Positivos / Resistencia a Medicamentos Antineoplásicos / ADP-Ribosil Ciclase 1 / Receptor de Morte Celular Programada 1 / Neoplasias Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Nat Immunol Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos