Bloom M B, Perry-Lalley D, Robbins P F, Li Y, el-Gamil M, Rosenberg S A, Yang J C
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Exp Med. 1997 Feb 3;185(3):453-9. doi: 10.1084/jem.185.3.453.
Recently, major advances have been made in the identification of antigens from human melanoma which are recognized by T cells. In spite of this, little is known about the optimal ways to use these antigens to treat patients with cancer. Progress in this area is likely to require accurate preclinical animal models, but the availability of such models has lagged behind developments in human tumor immunology. Whereas many of the identified human melanoma antigens are normal tissue differentiation proteins, analogous murine tumor antigens have not yet been identified. In this paper we identify a normal tissue differentiation antigen, tyrosinase-related protein 2 (TRP-2), expressed by the murine B16 melanoma which was found by screening a cDNA library from B16 with tumor-reactive cytotoxic T lymphocytes (CTL). A peptide conforming to the predicted MHC class I H2-Kb binding motif, TRP-2181-188, was identified as the major reactive epitope within TRP-2 recognized by these anti-B16 CTLs. By site-directed mutagenesis, it was shown that alteration of this epitope eliminated recognition of TRP-2. It was further demonstrated that a CTL line raised from splenocytes by repeated stimulation in vitro with this peptide could recognize B16 tumor and was therapeutic against 3-d-old established pulmonary metastases. The use of TRP-2 in a preclinical model of tumor immunotherapy may be helpful in suggesting optimal vaccination strategies for cancer therapy in patients.
最近，在识别可被T细胞识别的人类黑色素瘤抗原方面取得了重大进展。尽管如此，对于使用这些抗原治疗癌症患者的最佳方法却知之甚少。该领域的进展可能需要精确的临床前动物模型，但此类模型的可用性落后于人类肿瘤免疫学的发展。虽然许多已识别的人类黑色素瘤抗原是正常组织分化蛋白，但尚未鉴定出类似的鼠肿瘤抗原。在本文中，我们鉴定了一种正常组织分化抗原，即酪氨酸酶相关蛋白2（TRP-2），它由鼠B16黑色素瘤表达，是通过用肿瘤反应性细胞毒性T淋巴细胞（CTL）筛选B16的cDNA文库发现的。一种符合预测的MHC I类H2-Kb结合基序的肽，TRP-2181-188，被确定为这些抗B16 CTL识别的TRP-2内的主要反应性表位。通过定点诱变表明，该表位的改变消除了对TRP-2的识别。进一步证明，通过用该肽在体外反复刺激从脾细胞培养的CTL系能够识别B16肿瘤，并对3日龄已建立的肺转移具有治疗作用。在肿瘤免疫治疗的临床前模型中使用TRP-2可能有助于为癌症患者的治疗提出最佳的疫苗接种策略。
