PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer.
Immune escape describes a critical event whereby tumor cells adopt an immunoresistant phenotype to escape adaptive surveillance. We show that expression of a pivotal negative regulator of T-cell function, B7-H1, correlates with PI(3) kinase activation in breast and prostate cancer patients. B7-H1-mediated immunoresistance can be attenuated by inhibitors of the PI(3) kinase pathway, and is dependent on S6K1-mediated translational regulation of B7-H1 protein. Breast and prostate carcinoma cells with activated PI(3) kinase lose the immunoresistant phenotype after treatment with B7-H1 siRNA. Conversely, breast and prostate carcinoma cells with minimal PI(3) kinase activation adopt an immunoresistant phenotype when engineered to overexpress B7-H1 protein. These observations describe a mechanism for immune escape from tumor dormancy in humans that relates to oncogenesis.
Crane
C A
CA
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
Panner
A
A
Murray
J C
JC
Wilson
S P
SP
Xu
H
H
Chen
L
L
Simko
J P
JP
Waldman
F M
FM
Pieper
R O
RO
Parsa
A T
AT
D000230:Adenocarcinoma / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D060890:B7-H1 Antigen; D001943:Breast Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; D060890:B7-H1 Antigen; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D019893:Ribosomal Protein S6 Kinases; C423236:CD274 protein, human; C494929:PTEN protein, human