title: STAT1 interaction with E3-14.7K in monocytes affects the efficacy of oncolytic adenovirus.
abstract: Oncolytic viruses based on adenovirus type 5 (Ad5) have been developed as a new class of therapeutic agents for cancers that are resistant to conventional therapies. Clinical experience shows that these agents are safe, but virotherapy alone has not achieved long-term cure in cancer patients. The vast majority of oncolytic adenoviruses used in clinical trials to date have deletion of the E3B genes. It has been demonstrated that the antitumor potency of the E3B-deleted mutant (dl309) is inferior to adenovirus with E3B genes intact. Tumors treated with dl309 show markedly greater macrophage infiltration than E3B-intact adenovirus. However, the functional mechanisms for this were not previously known. Here, we demonstrate that deletion of E3B genes increases production of chemokines by monocytes after adenovirus infection and increases monocyte migration. The E3B 14,700-Da protein (E3B-14.7K) inhibits STAT1 function by preventing its phosphorylation and nuclear translocation. The STAT1 inhibitor, fludarabine, rescues the effect of E3B-14.7K deletion by downregulating target chemokine expression in human and murine monocytes and results in an enhanced antitumor efficacy with dl309 in vivo. These findings have important implications for clinical use of E3B-deleted oncolytic adenovirus and other E3B-deleted adenovirus vector-based therapy.
authors: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors: Emma
authors: E
authors: Spurrell
authors: Rathi
authors: R
authors: Gangeswaran
authors: Pengju
authors: P
authors: Wang
authors: Fengyu
authors: F
authors: Cao
authors: Dongling
authors: D
authors: Gao
authors: Baisui
authors: B
authors: Feng
authors: William
authors: W
authors: Wold
authors: Ann
authors: A
authors: Tollefson
authors: Nicholas R
authors: NR
authors: Lemoine
authors: Yaohe
authors: Y
authors: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000256:Adenoviridae / Q000378:metabolism / Q000502:physiology*; D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D018076:DNA, Complementary / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018613:Microscopy, Confocal; D009000:Monocytes / Q000378:metabolism*; D050504:Oncolytic Viruses / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D017503:Adenovirus E3 Proteins; D018076:DNA, Complementary; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014740:Vidarabine; C024352:fludarabine