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.

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
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Caspase 6