Combined Cytolytic Effects of a Vaccinia Virus Encoding a Single Chain Trimer of MHC-I with a Tax-Epitope and Tax-Specific CTLs on HTLV-I-Infected Cells in a Rat Model

Takashi Ohashi,Minoru Kidokoro,Takafumi Nakamura,Hisatoshi Shida,Xianfeng Zhang

doi:10.1155/2014/902478

Abstract

Adult T cell leukemia (ATL) is a malignant lymphoproliferative disease caused by human T cell leukemia virus type I (HTLV-I). To develop an effective therapy against the disease, we have examined the oncolytic ability of an attenuated vaccinia virus (VV), LC16m8Δ (m8Δ), and an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) line, 4O1/C8, against an HTLV-I-infected rat T cell line, FPM1. Our results demonstrated that m8Δ was able to replicate in and lyse tumorigenic FPM1 cells but was incompetent to injure 4O1/C8 cells, suggesting the preferential cytolytic activity toward tumor cells. To further enhance the cytolysis of HTLV-I-infected cells, we modified m8Δ and obtained m8Δ/RT1AlSCTax180L, which can express a single chain trimer (SCT) of rat major histocompatibility complex class I with a Tax-epitope. Combined treatment with m8Δ/RT1AlSCTax180L and 4O1/C8 increased the cytolysis of FPM1V.EFGFP/8R cells, a CTL-resistant subclone of FPM1, compared with that using 4O1/C8 and m8Δ presenting an unrelated peptide, suggesting that the activation of 4O1/C8 by m8Δ/RT1AlSCTax180L further enhanced the killing of the tumorigenic HTLV-I-infected cells. Our results indicate that combined therapy of oncolytic VVs with SCTs and HTLV-I-specific CTLs may be effective for eradication of HTLV-I-infected cells, which evade from CTL lysis and potentially develop ATL.

Highlights

Human T cell leukemia virus type I (HTLV-I) is etiologically linked to adult T cell leukemia (ATL) [1, 2] and a chronic progressive neurological disorder termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [3, 4]
Our results suggested the possible application of the combined use of oncolytic viruses presenting tumor antigens and tumor-specific cytotoxic T lymphocyte (CTL) for the treatments against tumors including ATL
Similar levels of significant cytolysis induction were observed in FPM1 cells infected with either m8Δ or mO at multiplicity of infection (MOI) 0.5

Summary

Introduction

Human T cell leukemia virus type I (HTLV-I) is etiologically linked to adult T cell leukemia (ATL) [1, 2] and a chronic progressive neurological disorder termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [3, 4]. Tax is known as a major target protein recognized by cytotoxic T lymphocyte (CTL) of HTLV-I carriers [7]. A number of studies have reported that CTL responses were activated in HAM/TSP patients but were weak in ATL patients, suggesting that the T cell response could be one of the important determinants of the disease manifestation [8]. Since HTLV-I Tax-specific CTL can recognize and lyse ATL cells in vitro [9], it is conceivable that the low CTL activity in ATL patients is disadvantageous as it may allow uncontrolled proliferation and evolution of HTLV-I-infected cells in vivo. The development of ATL has been reported in HTLV-I carriers who received immunosuppressants during organ transplantation [11]. Increase of Taxspecific CTLs observed in ATL patients treated successfully

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Conclusion