Prostate tumor cells infected with a recombinant influenza virus expressing a truncated NS1 protein activate cytolytic CD8+ cells to recognize noninfected tumor cells.
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/beta) 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/beta 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.
Efferson
Clay L
CL
Department of Gynecologic Oncology, Surgical Oncology, Breast Medical Oncology and Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Tsuda
Naotake
N
Kawano
Kouichiro
K
Nistal-Villán
Estanislao
E
Sellappan
Shankhar
S
Yu
Dihua
D
Murray
James L
JL
García-Sastre
Adolfo
A
Ioannides
Constantin G
CG
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D008213:Lymphocyte Activation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000502:physiology*
C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins