title: Implications for immunotherapy of tumor-mediated T-cell apoptosis associated with loss of the tumor suppressor PTEN in glioblastoma.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94123, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Waldron
authors.forename: Isaac
authors.initials: I
authors.lastname: Yang
authors.forename: Seunggu
authors.initials: S
authors.lastname: Han
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Michael E
authors.initials: ME
authors.lastname: Sughrue
authors.forename: Steven A
authors.initials: SA
authors.lastname: Mills
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
mesh_terms: 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
chemical_list: 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
references.citation: J Mol Med (Berl). 2003 May;81(5):281-7
references.pmid: 12721664
references.citation: Cancer Res. 2003 Nov 1;63(21):7462-7
references.pmid: 14612546
references.citation: Cancer. 2005 Nov 15;104(10):2084-91
references.pmid: 16208700
references.citation: J Immunother. 2009 Jul-Aug;32(6):585-92
references.pmid: 19483651
references.citation: Acta Neuropathol. 2003 Nov;106(5):479-85
references.pmid: 12904991
references.citation: Brain Res Brain Res Rev. 1995 Sep;21(2):128-51
references.pmid: 8866671
references.citation: Glia. 2001 Dec;36(3):391-405
references.pmid: 11746775
references.citation: J Neurosurg. 2004 Feb;100(2):310-9
references.pmid: 15086239
references.citation: Blood. 2004 Oct 1;104(7):2124-33
references.pmid: 15191948
references.citation: Nat Immunol. 2002 Nov;3(11):991-8
references.pmid: 12407406
references.citation: Neuroreport. 2005 Jul 13;16(10):1081-5
references.pmid: 15973152
references.citation: Nat Med. 2002 Aug;8(8):793-800
references.pmid: 12091876
references.citation: Nat Med. 1999 Dec;5(12):1365-9
references.pmid: 10581077
references.citation: Nat Med. 2007 Jan;13(1):84-8
references.pmid: 17159987