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Targeted inhibition of glycogen synthase kinase-3 using 9-ING-41 (elraglusib) enhances CD8 T-cell-reactivity against neuroblastoma cells.
Markovska, A; Somers, K; Guillaume, J; Melief, J; Mazar, A P; Schmitt, D M; Schipper, H S; Boes, M.
Afiliación
  • Markovska A; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3508 GA, Utrecht, The Netherlands.
  • Somers K; Lowy Cancer Research Centre, Children's Cancer Institute, UNSW Sydney, Sydney, NSW, Australia.
  • Guillaume J; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
  • Melief J; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3508 GA, Utrecht, The Netherlands.
  • Mazar AP; Karolinska Institutet, Stockholm, Sweden.
  • Schmitt DM; Actuate Therapeutics, Fort Worth, TX, 76107, USA.
  • Schipper HS; Actuate Therapeutics, Fort Worth, TX, 76107, USA.
  • Boes M; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3508 GA, Utrecht, The Netherlands.
Sci Rep ; 14(1): 21710, 2024 Sep 17.
Article en En | MEDLINE | ID: mdl-39289439
ABSTRACT
The prognosis of patients with high-risk neuroblastoma remains poor, partly due to inadequate immune recognition of the tumor. Neuroblastomas display extremely low surface MHC-I, preventing recognition by cytotoxic T lymphocytes (CTLs) and contributing to an immunosuppressive tumor microenvironment. Glycogen synthase kinase-3 beta (GSK-3ß) is involved in pathways that may affect the MHC-I antigen processing and presentation pathway. We proposed that therapeutic inhibition of GSK-3ß might improve the surface display of MHC-I molecules on neuroblastoma cells, and therefore tested if targeting of GSK-3ß using the inhibitor 9-ING-41 (Elraglusib) improves MHC-I-mediated CTL recognition. We analyzed mRNA expression data of neuroblastoma tumor datasets and found that non-MYCN-amplified neuroblastomas express higher GSK-3ß levels than MYCN-amplified tumors. In non-MYCN-amplified cells SH-SY5Y, SK-N-AS and SK-N-SH 9-ING-41 treatment enhanced MHC-I surface display and the expression levels of a subset of genes involved in MHC-I antigen processing and presentation. Further, 9-ING-41 treatment triggered increased STAT1 pathway activation, upstream of antigen presentation pathways in two of the three non-MYCN-amplified cell lines. Finally, in co-culture experiments with CD8 + T cells, 9-ING-41 improved immune recognition of the neuroblastoma cells, as evidenced by augmented T-cell activation marker levels and T-cell proliferation, which was further enhanced by PD-1 immune checkpoint inhibition. Our preclinical study provides experimental support to further explore the GSK-3ß inhibitor 9-ING-41 as an immunomodulatory agent to increase tumor immune recognition in neuroblastoma.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T CD8-positivos / Glucógeno Sintasa Quinasa 3 beta / Neuroblastoma Límite: Humans Idioma: En Revista: Sci Rep Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T CD8-positivos / Glucógeno Sintasa Quinasa 3 beta / Neuroblastoma Límite: Humans Idioma: En Revista: Sci Rep Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido