title: [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.affiliation: Department of Biology Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123 People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Department of Biology Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123 People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Biology Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123 People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Immunology, School of Basic Medicine and Life Sciences, Medical College of Soochow University, Suzhou, 215123 People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Biology Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123 People's Republic of China.|zliang@suda.edu.cn.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D002460:Cell Line; D002867:Chromones / Q000493:pharmacokinetics; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D009025:Morpholines / Q000493:pharmacokinetics; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D020123:Sirolimus / Q000493:pharmacokinetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000276:immunology / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; D000077191:Wortmannin; C475826:VTCN1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human
keywords: B7-H4; PI3K/Akt/mTOR; immunoresistance; subcellular distribution; tumor