Therapeutic effect of a T helper cell supported CTL response induced by a survivin peptide vaccine against murine cerebral glioma
Therapeutic effect of a T helper cell supported CTL response induced by a survivin peptide vaccine against murine cerebral glioma
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DOI：
10.1007/s00262-008-0510-9
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发表时间：
2008-12-01
影响因子：
5.8
通讯作者：
Fenstermaker, Robert A.
中科院分区：
文献类型：
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作者：
Ciesielski, Michael J.;Kozbor, Danuta;Fenstermaker, Robert A.
Survivin是一种肿瘤相关抗原（TAA），具有作为癌症疫苗靶点的巨大潜力。为了鉴定可能作为ctl介导的抗肿瘤反应靶点的survivin表位，我们评估了一系列在肽负载树突状细胞（DC）疫苗中与小鼠H2-Kb和人HLA-A*0201抗原结合的survivin肽。H2-K(b)阳性，C57BL/6小鼠接种同源，多肽负载的DC2.4细胞。通过流式细胞术筛选接种小鼠的脾细胞，检测二聚体H2-K(b): Ig与肽特异性CD8+ T细胞的结合。两种survivin肽（SVN57-64和SVN82-89）产生特异性CD8+ T细胞。我们选择专注于SVN57-64肽，因为该分子的该区域与人类survivin 100%同源。一个更大的肽（SVN53-67），包含多个I类表位和一个潜在的II类配体，能够引起CD8+ CTL和CD4+ T细胞的帮助。我们在具有survivin表达GL261脑胶质瘤的C57BL/6小鼠中使用肽负载DC疫苗检测了SVN(53-67) 15-mer肽的治疗模型。该疫苗产生了显著的CTL反应和辅助性T细胞相关细胞因子的产生，从而显著延长了生存期。SVN（53- 67）疫苗作为癌症疫苗的有效性明显高于SVN（57-64）核心表位，这强调了在单个肽中结合多个I类表位和相关细胞因子支持的潜在益处。
Survivin is a tumor-associated antigen (TAA) that has significant potential for use as a cancer vaccine target. To identify survivin epitopes that might serve as targets for CTL-mediated, anti-tumor responses, we evaluated a series of survivin peptides with predicted binding to mouse H2-Kb and human HLA-A*0201 antigens in peptide-loaded dendritic cell (DC) vaccines. H2-K(b)-positive, C57BL/6 mice were vaccinated using syngeneic, peptide-loaded DC2.4 cells. Splenocytes from vaccinated mice were screened by flow cytometry for binding of dimeric H2-K(b): Ig to peptide-specific CD8+ T cells. Two survivin peptides (SVN57-64 and SVN82-89) generated specific CD8+ T cells. We chose to focus on the SVN57-64 peptide because that region of the molecule is 100% homologous to human survivin. A larger peptide (SVN53-67), containing multiple class I epitopes, and a potential class II ligand, was able to elicit both CD8+ CTL and CD4+ T cell help. We tested the SVN(53-67) 15-mer peptide in a therapeutic model using a peptide-loaded DC vaccine in C57BL/6 mice with survivin-expressing GL261 cerebral gliomas. This vaccine produced significant CTL responses and helper T cell-associated cytokine production, resulting in a significant prolongation of survival. The SVN(53- 67) vaccine was significantly more effective than the SVN(57-64) core epitope as a cancer vaccine, emphasizing the potential benefit of incorporating multiple class I epitopes and associated cytokine support within a single peptide.