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PAK4 inhibition improves PD-1 blockade immunotherapy.
Abril-Rodriguez, Gabriel; Torrejon, Davis Y; Liu, Wei; Zaretsky, Jesse M; Nowicki, Theodore S; Tsoi, Jennifer; Puig-Saus, Cristina; Baselga-Carretero, Ignacio; Medina, Egmidio; Quist, Michael J; Garcia, Alejandro J; Senapedis, William; Baloglu, Erkan; Kalbasi, Anusha; Cheung-Lau, Gardenia; Berent-Maoz, Beata; Comin-Anduix, Begoña; Hu-Lieskovan, Siwen; Wang, Cun-Yu; Grasso, Catherine S; Ribas, Antoni.
Afiliação
  • Abril-Rodriguez G; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Torrejon DY; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Liu W; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Zaretsky JM; Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • Nowicki TS; Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA, USA.
  • Tsoi J; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Puig-Saus C; Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of California, Los Angeles, Los Angeles, USA.
  • Baselga-Carretero I; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Medina E; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Quist MJ; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Garcia AJ; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Senapedis W; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Baloglu E; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Kalbasi A; Karyopharm Therapeutics, Newton, MA, USA.
  • Cheung-Lau G; Karyopharm Therapeutics, Newton, MA, USA.
  • Berent-Maoz B; Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Comin-Anduix B; Department of Surgery, Division of Surgical Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Hu-Lieskovan S; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
  • Wang CY; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Grasso CS; Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Ribas A; Department of Surgery, Division of Surgical Oncology, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Cancer ; 1(1): 46-58, 2020.
Article em En | MEDLINE | ID: mdl-34368780
ABSTRACT
Lack of tumor infiltration by immune cells is the main mechanism of primary resistance to programmed cell death protein 1 (PD-1) blockade therapies for cancer. It has been postulated that cancer cell-intrinsic mechanisms may actively exclude T cells from tumors, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. Here, we show that p21-activated kinase 4 (PAK4) is enriched in non-responding tumor biopsies with low T cell and dendritic cell infiltration. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD-1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of anti-PD-1 with the PAK4 inhibitor KPT-9274 improved anti-tumor response compared with anti-PD-1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and a lack of response to PD-1 blockade, which could be reversed with PAK4 inhibition.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinases Ativadas por p21 / Receptor de Morte Celular Programada 1 / Inibidores de Checkpoint Imunológico / Imunoterapia / Neoplasias Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinases Ativadas por p21 / Receptor de Morte Celular Programada 1 / Inibidores de Checkpoint Imunológico / Imunoterapia / Neoplasias Idioma: En Ano de publicação: 2020 Tipo de documento: Article