Abstract
Survivin is a bifunctional protein that acts as a suppressor of apoptosis and plays a central role in cell division. The protein is strongly expressed in the most common human neoplasms, has prognostic relevance for some of them and appears to be involved in tumor cell resistance to anticancer agents and ionizing radiation. Recently, survivin has been reported to be abundantly overexpressed in malignant glioma. The present study is a report of a novel approach of targeting malignant with pSurvivin95-104-specific cytotoxic T-lymphocytes (CTLs). pSurvivin95-104-specific CTLs were induced from the peripheral blood lymphocytes (PBLs) of HLA-A2 positive healthy donors by multiple stimulations with W6/32 antibody-mediated artificial antigen-presenting cells (aAPCs) made by coating HLA-A2/pSurvivin95-104 tetramer mediated by W6/32 antibody, anti-CD28 antibody, 4-1BBL and CD83 molecules to cell-sized latex beads. After multiple stimulations and sorting, the expanded CTLs were analyzed for tetramer staining, IFN-γ production, CTL reactivity and adoptive immunotherapy experiments. Tetramer staining assay demonstrated the expanded CTLs specifically bound HLA-A2- pSurvivin95-104 tetramer. The CTLs specifically produced IFN-γ in response to W6/32 antibody-mediated aAPCs and exhibited specific lysis against T2 cells pulsed with the peptide and HLA-A2+ cells expressing pSurvivin95-104, while HLA-A2- cell lines that express survivin could not be recognized by the CTLs. The peptide-specific activity was inhibited by anti-HLA class I monoclonal antibody. Intravenous injection of the expanded pSurvivin95-104-specific CTLs into nonobese diabetic– severe combined immunodeficiency (NOD/SCID) mice harboring cells resulted in cells elimination, whereas transfer of control T-cells was ineffective. These results show the expanded CTLs specific for pSurvivin95-104 peptide could be a potential target of specific immunotherapy for HLA-A2 patients with malignant glioma
Highlights
Malignant glioma patients usually undergo debulking surgery followed by radiation and aggressive rounds of chemotherapy
We used W6/32 antibody-mediated artificial antigen-presenting cells made by coating human leukocyte antigen (HLA)-A2/pSurvivin95-104 tetramer mediated by W6/32 antibody, anti-CD28 antibody, 4-1BBL and CD83 molecules to cellsized latex beads to generate specific cytotoxic T-lymphocytes (CTLs) against malignant glioma from the peripheral blood lymphocytes (PBLs) of healthy donors in vitro, in which these CTL lysed HLA-A2+ glioma cells that expressed pSurvivin95-104 and could eliminate glioma cells in NOD/SCID mice
Before stimulation using W6/32 antibody-mediated pSurvivin95-104-specific artificial antigen-presenting cells (aAPCs), the frequency of CD8+ T-cells stained with HLA-A2/pSurvivin95-104 tetramers was 0.63%
Summary
Malignant glioma patients usually undergo debulking surgery followed by radiation and aggressive rounds of chemotherapy. Despite the majority of the tumors being removed or killed, no lasting and effective antitumor immunity is generated and the patients die from the tumor cells escaping or resisting those therapies. These failures lead many to believe that an aggressive combination of standard therapies, along with other biologically based therapies, is needed to successfully treat this cancer. The central nervous system (CNS), and tumors that arise therein, reside in an “immunologically privileged” site [1], some glioma patients were successfully treated by immunotherapy [2,3,4,5,6,7]. Immunotherapy for glioma is an attractive alternative treatment option
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