Implications for immunotherapy of tumor-mediated T-cell apoptosis associated with loss of the tumor suppressor PTEN in glioblastoma

James S. Waldron, Isaac Yang, Seunggu (Jude) Han, Tarik Tihan, Michael E. Sughrue, Steven A. Mills, Russell O. Pieper, Andrew T. Parsa

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The abŞişl.ty of glioma cells to escape the immune system remains a significant barrier to successful immunotherapy. Here we demonstrate that loss of the PTEN tumor suppressor gene, with associated activation of the PI3K/Akt/mTOR pathway, leads to a human glioma phenotype that induces autologous T-cell apoptosis upon contact. The PTEN status of pathologically confirmed glioblastoma specimens was defined, and primary cultures established after surgical resection of tumor from 26 patients. Autologous T-cells were isolated from these patients, and after T-cell activation was induced, these cells were co-cultured with matched autologous glioma cells, either alone, or after treatment with one of three inhibitors of the PI3K/Akt/mTOR pathway. When co-cultured with autologous T-cells, PTEN wild-type tumor cells induced apoptosis in a minimal number of activated T-cells (6-12% of T-cells), whereas tumors with PTEN loss induced much more profound levels of T-cell apoptosis (42-56% of T-cells). Prior treatment of PTEN-deficient tumor cells with specific inhibitors of the PI3K/Akt/mTOR pathway diminished T-cell apoptosis to levels seen after co-culture with wild-type PTEN tumor cells, suggesting that PTEN loss confers this immunoresistant phenotype through the PI3K/Akt/mTOR pathway. These results suggest that PTEN-deficient glioblastoma patients are suboptimal candidates for immunotherapy. In addition, our results raise the possibŞişl.ty of combining T-cell based immunotherapy protocols with clinical inhibitors of the PI3K/Akt/mTOR pathway.

Original languageEnglish (US)
Pages (from-to)1543-1547
Number of pages5
JournalJournal of Clinical Neuroscience
Volume17
Issue number12
DOIs
Publication statusPublished - Dec 1 2010
Externally publishedYes

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Keywords

  • Akt
  • Immunoresistance
  • PI3K
  • PTEN tumor suppressor gene

ASJC Scopus subject areas

  • Surgery
  • Neurology
  • Clinical Neurology
  • Physiology (medical)

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