Generation of antigen-specific CTL responses using RGS1 mRNA transfected dendritic cells
Generation of antigen-specific CTL responses using RGS1 mRNA transfected dendritic cells
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DOI：
10.1007/s00262-008-0486-5
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发表时间：
2008-10-01
影响因子：
5.8
通讯作者：
Brossart, Peter
中科院分区：
文献类型：
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作者：
Gruenebach, Frank;Erndt, Stefanie;Brossart, Peter
肿瘤免疫学和肿瘤相关抗原(TAAs)的研究进展为开发治疗恶性疾病的新型免疫疗法提供了基础。为了识别新的TAA，我们对(异类)组织进行了比较微阵列分析，发现G蛋白信号调节因子1(RGS1)在肾细胞癌(RCC)组织中广泛上调。为了研究该分子作为一种新的、广泛适用的TAA的可能功能，合成了全长RGS1-mRNA，用于单核细胞来源的树突状细胞(DC)的转染。这些修饰的抗原提呈细胞(APC)被用来在体外诱导RGS1特异性细胞毒性T细胞(CTL)。从几名健康供者和一名慢性淋巴细胞白血病(CLL)患者身上获得的CTL对内源性表达RGS1蛋白的肿瘤细胞(包括肾细胞癌、黑色素瘤、卵巢癌和原代自体CLL母细胞)具有抗原特异性和人类白细胞抗原A2和A3限制性的杀伤活性。综上所述，我们的研究表明，RNA转基因DC体外诱导RGS1特异性CTL是可行和高效的。由于该分子在多种恶性肿瘤中(过度)表达，在针对表达RGS1的肿瘤细胞的癌症疫苗的背景下，它可能代表着一种有趣的新的TAA。
Advances in tumor immunology and Identification of tumor-associated antigens (TAAs) provide a basis for the development of novel immunotherapies to treat malignant diseases. In order to identify novel TAAs, we performed comparative microarray analysis of (heterogeneous) tissues and found regulator of G protein-signaling 1 (RGS1) extensively up-regulated in renal cell carcinoma (RCC) tissues. To examine the possible function of this molecule as a novel, broadly applicable TAA, synthetic full-length RGS1-mRNA was synthesized for the transfection of monocyte-derived dendritic cells (DCs). These modified antigen-presenting cells (APCs) were then used to induce RGS1-specific cytotoxic T cells (CTLs) in vitro. The CTLs generated from several healthy donors and a patient with chronic lymphocytic leukemia (CLL) elicited an antigen-specific and HLA-A2- and -A3-restricted cytolytic activity against tumor cells endogenously expressing the RGS1 protein including renal cell carcinomas (RCCs), melanoma, ovarian carcinoma and the primary autologous CLL-blasts. In conclusion, our study demonstrates that the in vitro induction of RGS1-specific CTLs by RNA-transfected DCs is feasible and highly effective. Since this molecule is (over-) expressed in a broad variety of malignancies it might represent an interesting novel TAA in the context of cancer vaccines designed to target RGS1 expressing tumor cells.