Santomasso Bianca D, Roberts Wendy K, Thomas Ashby, Williams Travis, Blachère Nathalie E, Dudley Mark E, Houghton Alan N, Posner Jerome B, Darnell Robert B
Howard Hughes Medical Institute, Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19073-8. doi: 10.1073/pnas.0704336104.
The onconeural antigens appear to serve as tumor rejection antigens in the paraneoplastic neurologic disorders. Here, we used an unbiased peptide binding screen, followed by studies in HLA-A2.1 transgenic mice to identify naturally processed HLA-A2.1 restricted epitopes of the paraneoplastic cerebellar degeneration breast/ovarian cancer antigen cdr2. These mice were used to clone high-avidity cdr2-specific CD8(+) T cells that recognize human tumor cells presenting endogenously loaded MHC class I-cdr2 peptide. T cells with this specificity were detected in the peripheral blood of two HLA-A2.1(+) paraneoplastic cerebellar degeneration patients. We cloned T cell receptor (TCR) alpha and beta genes from cdr2-specific T cells; electroporation of RNA encoding this TCR turned nonreactive donor T cells into efficient killers of human cdr2-expressing tumor cells. Cloned cdr2-specific TCR genes provide a clinically relevant means for immunologic targeting of human gynecologic cancers.
肿瘤神经抗原似乎在副肿瘤性神经系统疾病中充当肿瘤排斥抗原。在此，我们采用无偏差的肽结合筛选，随后在HLA - A2.1转基因小鼠中进行研究，以鉴定副肿瘤性小脑变性乳腺癌/卵巢癌抗原cdr2的天然加工的HLA - A2.1限制性表位。这些小鼠用于克隆高亲和力的cdr2特异性CD8(+) T细胞，这些T细胞可识别呈递内源性负载的MHC I类 - cdr2肽的人肿瘤细胞。在两名HLA - A2.1(+)副肿瘤性小脑变性患者的外周血中检测到具有这种特异性的T细胞。我们从cdr2特异性T细胞中克隆了T细胞受体（TCR）α和β基因；将编码该TCR的RNA电穿孔可使无反应性的供体T细胞转变为人类cdr2表达肿瘤细胞的高效杀伤细胞。克隆的cdr2特异性TCR基因提供了一种针对人类妇科癌症进行免疫靶向的临床相关手段。
