[B7-H4-mediated immunoresistance is supressed by PI3K/Akt/mTOR pathway inhibitors].

Abstract

B7-H4 plays an important role in tumor immune evasion. In previous studies we have found that B7-H4 can translocate to the nucleus, and the exposure to PI3K inhibitor Ly294002 affects B7-H4 subcellular distribution. In this study we report the role of PI3K/Akt pathway in the B7-H4 subcellular distribution and the effect of PI3K/Akt inhibitors on B7-H4-mediated immunoresistance. The involvement of PI3K/Akt pathway in B7-H4 subcellular distribution was evident in experiments with wortmannin, while MDM2 inhibitor nutlin-3 and the mTOR inhibitor rapamycin were used to dissect the signaling downstream of Akt. Wortmannin and rapamycin demonstrated similar effects on B7-H4 subcellular distribution. Exposure to any of these inhibitors decreased levels of membrane B7-H4 while at the same time inducing its nuclear accumulation, while exposure to nutlin-3 had no effect on B7-H4 subcellular distribution. In the T cell proliferation assay, both wortmannin and rapamycin effectively inhibited B7-H4 WT/293 cells-mediated T cell proliferation while exerting no effect on Mock/293 cells. PI3K/Akt/mTOR plays a role in B7-H4 subcellular distribution, while MDM2 does not take part in it. Moreover, we show that wortmannin and rapamycin inhibit B7-H4-mediated tumor immunoresistance through regulating B7-H4 subcellular distribution. Taken together, these results suggest that PI3K/Akt/mTOR inhibitors might be used for adjuvant therapy aimed at inhibition of immune evasion.

• Authors: S Zeng, H Song, Y Chen, W Xie, L Zhang
• Journal: Molekuliarnaia biologiia (Mol Biol (Mosk)) 2016 Nov-Dec Vol. 50 Issue 6 Pg. 1007-1013 ISSN: 0026-8984 [Print] Russia (Federation)
• PMID: 28064317 (Publication Type: Journal Article)

Chemical References

• Androstadienes
• Chromones
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• V-Set Domain-Containing T-Cell Activation Inhibitor 1
• VTCN1 protein, human
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Cell Line
• Chromones (pharmacokinetics)
• Humans
• Immune Tolerance (drug effects)
• Morpholines (pharmacokinetics)
• Phosphatidylinositol 3-Kinases (immunology, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (immunology, metabolism)
• Signal Transduction (drug effects, immunology)
• Sirolimus (pharmacokinetics)
• T-Lymphocytes (immunology, metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, immunology, metabolism)
• V-Set Domain-Containing T-Cell Activation Inhibitor 1 (immunology, metabolism)
• Wortmannin