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CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment.
Seyfrid, Mathieu; Maich, William Thomas; Shaikh, Vaseem Muhammad; Tatari, Nazanin; Upreti, Deepak; Piyasena, Deween; Subapanditha, Minomi; Savage, Neil; McKenna, Dillon; Mikolajewicz, Nicholas; Han, Hong; Chokshi, Chirayu; Kuhlmann, Laura; Khoo, Amanda; Salim, Sabra Khalid; Archibong-Bassey, Blessing; Gwynne, William; Brown, Kevin; Murtaza, Nadeem; Bakhshinyan, David; Vora, Parvez; Venugopal, Chitra; Moffat, Jason; Kislinger, Thomas; Singh, Sheila.
Afiliação
  • Seyfrid M; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
  • Maich WT; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Shaikh VM; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
  • Tatari N; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Upreti D; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
  • Piyasena D; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Subapanditha M; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Savage N; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • McKenna D; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Mikolajewicz N; Department of Molecular Genetics - Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • Han H; Department of Molecular Genetics - Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • Chokshi C; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Kuhlmann L; Department of Medical Biophysics, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
  • Khoo A; Department of Medical Biophysics, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
  • Salim SK; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Archibong-Bassey B; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
  • Gwynne W; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
  • Brown K; Department of Molecular Genetics - Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • Murtaza N; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Bakhshinyan D; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • Vora P; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
  • Venugopal C; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
  • Moffat J; Department of Molecular Genetics - Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • Kislinger T; Department of Medical Biophysics, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
  • Singh S; Department of Surgery, McMaster University, Hamilton, Ontario, Canada ssingh@mcmaster.ca.
J Immunother Cancer ; 10(1)2022 01.
Article em En | MEDLINE | ID: mdl-35017149
ABSTRACT

PURPOSE:

Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, we identify CD70 as a potential therapeutic target for recurrent GBM CSCs. EXPERIMENTAL

DESIGN:

In the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We use CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate CD70's role in GBM. Next, we developed and tested an anti-CD70 chimeric antigen receptor (CAR)-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples.

RESULTS:

CD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations, notably putative M1 macrophages and CD4 T cells.

CONCLUSION:

CD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable polytherapeutic avenue to co-target both GBM and its TIME.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2022 Tipo de documento: Article