The antitumor effect of human cord blood-derived dendritic cells modified by the livin α gene

The antitumor effect of human cord blood-derived dendritic cells modified by the livin α gene in lung cancer cell lines

ONCOLOGY REPORTS 29: 619-627, 2013

The antitumor effect of human cord blood-derived dendritic cells modified by the livin α gene in lung cancer cell lines

HAO CHEN1,2, YANG JIN1,2, TING CHEN1,2, MINGQIANG ZHANG1,2,

WANLI MA1,2, XIANZHI XIONG1,2 and XIAONAN TAO1,2

Department of Respiratory Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan; 2Key Laboratory of Pulmonary

Diseases of the Ministry of Health of China, Wuhan, Hubei 430022, P.R. China

Received August 1, 2012; Accepted August 16, 2012

DOI: 10.3892/or.2012.2133

Abstract. The growth of malignant tumors is associated with mechanisms of immune escape and inhibition of apoptosis. Livin is a novel member of the inhibitors of apoptosis (IAP) protein family that inhibits cell apoptosis. Livin is specifically expressed by the majority of tumor cells, but it is not expressed in normal adult tissues. In this study, we used umbilical cord blood (UCB)-derived dendritic cells (DCs) infected with a recombinant adenovirus encoding the livin gene as a vaccine to activate effector cells such as cytotoxic T lymphocytes (CTLs) to recognize and kill livin-expressing cancer cells in vitro as an improved strategy for overcoming the ability of these cancer cells to escape apoptosis and antitumor immune responses. We employed interferon-γ (IFN-γ) enzyme-linked immunospot assays to confirm that our immunization strategy induced an antigen-specific reaction to livin and flow cyto-metric analysis of staining with Annexin V and PI to measure the cytotoxic activity of the effector cells against the livin-expressing lung cancer cell lines A549 and H460. Our results show that the recombinant adenovirus was able to promote the maturation of the UCB-derived DCs. This DC vaccine could activate antigen-specific T cells to produce IFN-γ upon recog-nition of livin peptide in the context of the appropriate HLA molecule. The antigen-specific T cells mediate significant cytotoxicity against the cancer cells, but are unlikely to cause an autoimmune reaction against the human bronchial epithelia cells (HBE), which do not express livin.Introduction

The acquisition of resistance to apoptosis and the ability to escape from immunological surveillance are the hallmarks of tumor cells (1,2). The inhibitors of apoptosis proteins

(IAPs) inhibit apoptosis by interacting with the pro-apoptotic caspases via their baculoviral IAP repeat (BIR) (3). Previous studies indicated that downregulating the expression of IAPs is beneficial to the treatment of cancer and may be a neces-sary component of the antitumor activities of conventional treatments such as radiation and chemotherapy (4-6). Livin is a novel member of the IAP family; it has two isoforms that are termed livin α (298-amino acid residues) and livin β (280- amino acid residues). Each isoform contains a single BIR domain and a RING finger domain (7). In contrast to other members of the IAP family, such as cIAP-1, cIAP-2, XIAP and NAIP, which are expressed at low levels in normal adult tissues, livin is not expressed in normal adult tissues but is overexpressed in primary lung cancer and other malignant tumor cells (8,9). Livin expression levels correlate to some degree with the stage and pathological type of the cancer, and livin expression can induce tumor cells to become resistant to antineoplastic drugs and are characteristic of a cancer with a poor prognosis (9-12). Evidence suggests that interfering with either the expression of the livin gene or the function of the livin protein could provide a potential therapeutic avenue to induce apoptosis in tumor cells and to significantly improve antitumor responses (13-15).

Since anti-livin autoantibodies have been identified in the serum of the majority of cancer patients, immunologic tolerance to livin is thought to be very weak (16,17), making livin a promising candidate target for immunotherapy. Dendritic cells (DCs) are classic antigen-presenting cells (APCs) and can efficiently take up and present tumor antigens as well as provide the co-stimulatory molecules required to activate naive T lymphocytes (18,19). In addi-tion to antigen modulation and immune evasion (20), cancer cells may cause DCs to downregulate their expres-sion of MHC class I molecules when the two cell types are co-cultured (21). This reduces the ability of the DCs to activate CD8+ T cells and leads to immune escape. In the present study, we showed that DCs that have been modified to express the livin α gene could provide stable presentation of livin epitopes and could induce T-cell activation. We developed a cell-transfer therapy based on these observations in which pre-sensitized tumor-specific effector cells were expanded in vitro and transplanted into

1

Correspondence to: Professor Xiaonan Tao, Department of Respiratory

Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. ChinaE-mail: taoxn2004@http://www.wendangwang.com

Key words: livin α gene, DC vaccine, recombinant adenovirus, lung

cancer

The antitumor effect of human cord blood derived dendritic cells modified by the livin α gene相关文档

最新文档

返回顶部