Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma

Andrew T Parsa; James S Waldron; Amith Panner; Courtney A Crane; Ian F Parney; Jeffrey J Barry; Kristine E Cachola; Joseph C Murray; Tarik Tihan; Michael C Jensen; Paul S Mischel; David Stokoe; Russell O Pieper

doi:10.1038/nm1517

Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma

Nat Med. 2007 Jan;13(1):84-8. doi: 10.1038/nm1517. Epub 2006 Dec 10.

Authors

Andrew T Parsa¹, James S Waldron, Amith Panner, Courtney A Crane, Ian F Parney, Jeffrey J Barry, Kristine E Cachola, Joseph C Murray, Tarik Tihan, Michael C Jensen, Paul S Mischel, David Stokoe, Russell O Pieper

Affiliation

¹ Department of Neurological Surgery, University of California San Francisco, 505 Parnassus Avenue, M-779, San Francisco, California 94143, USA. [email protected]

PMID: 17159987
DOI: 10.1038/nm1517

Abstract

Cancer immunoresistance and immune escape may play important roles in tumor progression and pose obstacles for immunotherapy. Expression of the immunosuppressive protein B7 homolog 1 (B7-H1), also known as programmed death ligand-1 (PD-L1), is increased in many pathological conditions, including cancer. Here we show that expression of the gene encoding B7-H1 increases post transcriptionally in human glioma after loss of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. Tumor specimens from individuals with glioblastoma multiforme (GBM) had levels of B7-H1 protein that correlated with PTEN loss, and tumor-specific T cells lysed human glioma targets expressing wild-type PTEN more effectively than those expressing mutant PTEN. These data identify a previously unrecognized mechanism linking loss of the tumor suppressor PTEN with immunoresistance, mediated in part by B7-H1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Analysis of Variance
Antibodies, Monoclonal / pharmacology
Antigens, CD / genetics*
Antigens, CD / immunology
Antigens, CD / metabolism
B7-H1 Antigen
Blotting, Western
Caspase 6 / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Enzyme Activation / drug effects
Flow Cytometry
Glioblastoma / genetics
Glioblastoma / metabolism
Glioblastoma / pathology
Glioma / genetics
Glioma / metabolism
Glioma / pathology*
Humans
Mutation
PTEN Phosphohydrolase / genetics*
PTEN Phosphohydrolase / metabolism
Protein Kinases / metabolism
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Ribosomal Protein S6 Kinases / genetics
Ribosomal Protein S6 Kinases / metabolism
Signal Transduction / drug effects
TOR Serine-Threonine Kinases
Transfection

Substances

Antibodies, Monoclonal
Antigens, CD
B7-H1 Antigen
CD274 protein, human
Protein Kinases
MTOR protein, human
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase
PTEN protein, human
Caspase 6