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Journal of Virology, January 2006, p. 383-394, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.383-394.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Prostate Tumor Cells Infected with a Recombinant Influenza Virus Expressing a Truncated NS1 Protein Activate Cytolytic CD8+ Cells To Recognize Noninfected Tumor Cells{dagger}

Clay L. Efferson,1,{ddagger} Naotake Tsuda,1,{ddagger} Kouichiro Kawano,1 Estanislao Nistal-Villán,2,3 Shankhar Sellappan,4 Dihua Yu,4 James L. Murray,5 Adolfo García-Sastre,2* and Constantin G. Ioannides1

Department of Gynecologic Oncology, Surgical Oncology, Breast Medical Oncology and Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030,1 Department of Microbiology,2 Microbiology Graduate School Training Program, Mount Sinai School of Medicine, New York, New York 100293

Received 14 April 2005/ Accepted 28 September 2005

Many viral oncolytic approaches against cancer are based on the ability of specific viruses to replicate in tumors expressing components of the constitutively activated Ras/mitogen-activated protein kinase (MAPK) pathways and/or inhibited or dysregulated alpha/beta interferon (IFN-{alpha}/ß) response pathways. A major issue when considering these approaches is their applicability to tumors that lack activated Ras. To identify the effector mechanisms activated by oncolytic viruses, we investigated inhibition of proliferation of the prostate cancer line LNCap by the recombinant TR-NS1 influenza A virus, a genetically attenuated influenza A/PR8/34 virus expressing a truncated nonstructural protein (NS1) of 126 amino acids. LNCap cells lack constitutively activated MAPK, extracellular signal-regulated kinase (ERK), and p38 and are resistant to death by IFN-{alpha}. Truncation of the NS1 protein of influenza viruses is known to result in viral attenuation due to a reduced ability of the NS1 to inhibit the IFN-{alpha}/ß response. Infection with TR-NS1 virus rapidly activated ERK-1 more than ERK-2 in LNCap cells. Importantly, TR-NS1 virus infection transiently inhibited cell proliferation and induced apoptosis in LNCap cells. Addition of peripheral blood mononuclear cells (PBMC) and interleukin 12 (IL-12) to TR-NS1 virus-infected LNCap cells (TR-NS1-LNCap) resulted in faster elimination of TR-NS1-LNCap cells compared with LNCap cells. Moreover, TR-NS1-LNCap cells induced IFN-{gamma} in PBMC. The levels of IFN-{gamma} were amplified by IL-12. TR-NS1-LNCap cells also induced tumor-lytic cytotoxic T lymphocytes (CTL). These CTL lysed noninfected LNCap cells in a CD8-dependent manner. Activation of cellular immunity to tumor cells by viruses is an intriguing effector pathway, which should be especially significant for elimination of human tumors that lack activated Ras.

* Corresponding author. Mailing address: Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029. Phone: (212) 241-7769. Fax: (212) 534-1684. E-mail: adolfo.garcia-sastre{at}mssm.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} These two authors contributed equally to this work.

Journal of Virology, January 2006, p. 383-394, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.383-394.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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