Implications for immunotherapy of tumor-mediated T-cell apoptosis associated with loss of the tumor suppressor PTEN in glioblastoma.
The ability 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 possibility of combining T-cell based immunotherapy protocols with clinical inhibitors of the PI3K/Akt/mTOR pathway.
Waldron
James S
JS
Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94123, USA.
Yang
Isaac
I
Han
Seunggu
S
Tihan
Tarik
T
Sughrue
Michael E
ME
Mills
Steven A
SA
Pieper
Russell O
RO
Parsa
Andrew T
AT
D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism
D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human
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