Activation of Akt as a mechanism for tumor immune evasion.
Immune evasion is an important reason why the immune system cannot control tumor growth. To elucidate the mechanism for tumor immune evasion, we generated an immune-resistant human papillomavirus type 16 (HPV-16) E7-expressing tumor cell line by subjecting a susceptible tumor cell line to multiple rounds of in vivo immune selection with an E7-specific vaccine. Comparison of parental and immune-resistant tumors revealed that Akt is highly activated in the immune-resistant tumors. Retroviral transfer of a constitutively active form of Akt into the parental tumor significantly increased its resistance against E7-specific CD8(+) T-cell mediated apoptosis. The observed resistance against apoptosis was found to be associated with the upregulation of antiapoptotic molecules. We also observed that intratumoral injection of an Akt inhibitor enhanced the therapeutic efficacy of E7-specific vaccine or E7-specific CD8(+) T-cell adoptive transfer against the immune-resistant tumors. Thus, our data indicate that the activation of PI3K/Akt pathway represents a new mechanism of immune escape and has important implications for the development of a novel strategy in cancer immunotherapy against immune-resistant tumor cells.
Noh
Kyung Hee
KH
Divison of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
Kang
Tae Heung
TH
Kim
Jin Hee
JH
Pai
Sara I
SI
Lin
Ken Y
KY
Hung
Chien-Fu
CF
Wu
T-C
TC
Kim
Tae Woo
TW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014611:Vaccination; D000096926:Benzenesulfonamides
D002747:Chlorpropamide; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C111224:API 2; D000096926:Benzenesulfonamides