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PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma.
Liu, Xian-De; Kong, Wen; Peterson, Christine B; McGrail, Daniel J; Hoang, Anh; Zhang, Xuesong; Lam, Truong; Pilie, Patrick G; Zhu, Haifeng; Beckermann, Kathryn E; Haake, Scott M; Isgandrova, Sevinj; Martinez-Moczygemba, Margarita; Sahni, Nidhi; Tannir, Nizar M; Lin, Shiaw-Yih; Rathmell, W Kimryn; Jonasch, Eric.
Afiliação
  • Liu XD; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. xliu10@mdanderson.org.
  • Kong W; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Peterson CB; Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 200127.
  • McGrail DJ; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Hoang A; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Zhang X; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Lam T; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Pilie PG; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Zhu H; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Beckermann KE; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Haake SM; Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
  • Isgandrova S; Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
  • Martinez-Moczygemba M; Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, 77030, USA.
  • Sahni N; Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, 77030, USA.
  • Tannir NM; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, 78957, USA.
  • Lin SY; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Rathmell WK; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • Jonasch E; Vanderbilt-Ingram Cancer Center, Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Nat Commun ; 11(1): 2135, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358509
ABSTRACT
A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.
Assuntos
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Carcinoma de Células Renais / Proteínas de Ligação a DNA / Neoplasias Renais Tipo de estudo: Estudo prognóstico / Fatores de risco Limite: Animais / Feminino / Humanos Idioma: Inglês Revista: Nat Commun Assunto da revista: Biologia / Ciência Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Carcinoma de Células Renais / Proteínas de Ligação a DNA / Neoplasias Renais Tipo de estudo: Estudo prognóstico / Fatores de risco Limite: Animais / Feminino / Humanos Idioma: Inglês Revista: Nat Commun Assunto da revista: Biologia / Ciência Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos