STAT1 Interaction with E3-14.7K in Monocytes Affects the Efficacy of Oncolytic Adenovirus

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2013 Dec 17

PMID 24335311

Citations 9

Authors

Emma Spurrell

Rathi Gangeswaran

Pengju Wang

Fengyu Cao

Dongling Gao

Baisui Feng

William Wold

Ann Tollefson

Nicholas R Lemoine

Yaohe Wang

Affiliations

Soon will be listed here.

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.

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References

Muruve D, Barnes M, Stillman I, Libermann T . Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther. 1999; 10(6):965-76. DOI: 10.1089/10430349950018364. View

Shisler J, Yang C, Walter B, Ware C, Gooding L . The adenovirus E3-10.4K/14.5K complex mediates loss of cell surface Fas (CD95) and resistance to Fas-induced apoptosis. J Virol. 1997; 71(11):8299-306. PMC: 192288. DOI: 10.1128/JVI.71.11.8299-8306.1997. View

Didcock L, Young D, Goodbourn S, Randall R . The V protein of simian virus 5 inhibits interferon signalling by targeting STAT1 for proteasome-mediated degradation. J Virol. 1999; 73(12):9928-33. PMC: 113042. DOI: 10.1128/JVI.73.12.9928-9933.1999. View

Prestwich R, Harrington K, Pandha H, Vile R, Melcher A, Errington F . Oncolytic viruses: a novel form of immunotherapy. Expert Rev Anticancer Ther. 2008; 8(10):1581-8. PMC: 2729453. DOI: 10.1586/14737140.8.10.1581. View

Horwitz M . Function of adenovirus E3 proteins and their interactions with immunoregulatory cell proteins. J Gene Med. 2004; 6 Suppl 1:S172-83. DOI: 10.1002/jgm.495. View

Yarilina A, Park-Min K, Antoniv T, Hu X, Ivashkiv L . TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes. Nat Immunol. 2008; 9(4):378-87. DOI: 10.1038/ni1576. View

Srikiatkhachorn A, Chintapalli J, Liu J, Jamaluddin M, Harrod K, Whitsett J . Interference with intraepithelial TNF-α signaling inhibits CD8(+) T-cell-mediated lung injury in influenza infection. Viral Immunol. 2010; 23(6):639-45. PMC: 2991178. DOI: 10.1089/vim.2010.0076. View

Ikeda K, Wakimoto H, Ichikawa T, Jhung S, Hochberg F, Louis D . Complement depletion facilitates the infection of multiple brain tumors by an intravascular, replication-conditional herpes simplex virus mutant. J Virol. 2000; 74(10):4765-75. PMC: 111999. DOI: 10.1128/jvi.74.10.4765-4775.2000. View

Krajcsi P, Dimitrov T, Hermiston T, Tollefson A, Ranheim T, Vande Pol S . The adenovirus E3-14.7K protein and the E3-10.4K/14.5K complex of proteins, which independently inhibit tumor necrosis factor (TNF)-induced apoptosis, also independently inhibit TNF-induced release of arachidonic acid. J Virol. 1996; 70(8):4904-13. PMC: 190440. DOI: 10.1128/JVI.70.8.4904-4913.1996. View

10.

Leonard G, Sen G . Effects of adenovirus E1A protein on interferon-signaling. Virology. 1996; 224(1):25-33. DOI: 10.1006/viro.1996.0503. View

11.

Guo J, Hayashi J, Seeger C . West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005; 79(3):1343-50. PMC: 544142. DOI: 10.1128/JVI.79.3.1343-1350.2005. View

12.

Ohmori Y, Wyner L, Narumi S, Armstrong D, STOLER M, Hamilton T . Tumor necrosis factor-alpha induces cell type and tissue-specific expression of chemoattractant cytokines in vivo. Am J Pathol. 1993; 142(3):861-70. PMC: 1886781. View

13.

Garber K . China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst. 2006; 98(5):298-300. DOI: 10.1093/jnci/djj111. View

14.

Sohn S, Hearing P . Adenovirus sequesters phosphorylated STAT1 at viral replication centers and inhibits STAT dephosphorylation. J Virol. 2011; 85(15):7555-62. PMC: 3147932. DOI: 10.1128/JVI.00513-11. View

15.

Frank D, Mahajan S, Ritz J . Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med. 1999; 5(4):444-7. DOI: 10.1038/7445. View

16.

Fulci G, Dmitrieva N, Gianni D, Fontana E, Pan X, Lu Y . Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses. Cancer Res. 2007; 67(19):9398-406. PMC: 2850558. DOI: 10.1158/0008-5472.CAN-07-1063. View

17.

Zsengeller Z, Otake K, Hossain S, Berclaz P, Trapnell B . Internalization of adenovirus by alveolar macrophages initiates early proinflammatory signaling during acute respiratory tract infection. J Virol. 2000; 74(20):9655-67. PMC: 112398. DOI: 10.1128/jvi.74.20.9655-9667.2000. View

18.

Ikeda K, Ichikawa T, Wakimoto H, Silver J, Deisboeck T, Finkelstein D . Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. Nat Med. 1999; 5(8):881-7. DOI: 10.1038/11320. View

19.

Wang Y, Hallden G, Hill R, Anand A, Liu T, Francis J . E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models. Nat Biotechnol. 2003; 21(11):1328-35. DOI: 10.1038/nbt887. View

20.

Gooding L, Elmore L, Tollefson A, BRADY H, Wold W . A 14,700 MW protein from the E3 region of adenovirus inhibits cytolysis by tumor necrosis factor. Cell. 1988; 53(3):341-6. DOI: 10.1016/0092-8674(88)90154-7. View