Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma.
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.
Parsa
Andrew T
AT
Department of Neurological Surgery, University of California San Francisco, 505 Parnassus Avenue, M-779, San Francisco, California 94143, USA. parsaa@neurosurg.ucsf.edu
Waldron
James S
JS
Panner
Amith
A
Crane
Courtney A
CA
Parney
Ian F
IF
Barry
Jeffrey J
JJ
Cachola
Kristine E
KE
Murray
Joseph C
JC
Tihan
Tarik
T
Jensen
Michael C
MC
Mischel
Paul S
PS
Stokoe
David
D
Pieper
Russell O
RO
D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen; D015153:Blotting, Western; D053178:Caspase 6 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014162:Transfection
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053178:Caspase 6