Palmowski Michael, Salio Mariolina, Dunbar Rod P, Cerundolo Vincenzo
Weatherall Institute of Molecular Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Immunol Rev. 2002 Oct;188:155-63. doi: 10.1034/j.1600-065x.2002.18814.x.
Progress in human tumor immunology has recently been accelerated by new assays for antigen-specific cytotoxic T lymphocytes (CTLs). We have used tetrameric MHC class I complexes (tetramers) to study melanoma-specific CTLs both in vivo and in vitro, and have utilized the results to optimize vaccination strategies for patients. Tetramers have provided some of the best evidence to date that CTL responses against melanoma antigens arise spontaneously in patients. However, CTL responses to common (nonmutated) melanoma epitopes are generally weak or localized, and occur mostly in advanced metastatic disease, hence justifying early immunotherapeutic approaches. These observations led us to design a polyvalent vaccine construct for early administration to melanoma patients at high risk of progression. To compare possible vaccination protocols, we encoded this construct in several different vectors, and developed novel tetramers to track responses to the human melanoma epitopes in transgenic mice. Priming and boosting with the same poly-epitope construct encoded in heterologous vectors led to the expansion of CTLs with a single dominant specificity. Separating the antigens for independent presentation by antigen-presenting cells reversed the effect of immunodominance and induced a powerful polyvalent CTL response. These results provide important pointers for future vaccination trials, and tetramers will form an important tool in the immunomonitoring of these clinical studies.
针对抗原特异性细胞毒性T淋巴细胞（CTL）的新检测方法最近加速了人类肿瘤免疫学的进展。我们已使用四聚体MHC I类复合物（四聚体）在体内和体外研究黑色素瘤特异性CTL，并利用这些结果为患者优化疫苗接种策略。四聚体提供了迄今为止一些最佳证据，证明患者体内会自发产生针对黑色素瘤抗原的CTL反应。然而，CTL对常见（未突变）黑色素瘤表位的反应通常较弱或局限，且大多发生在晚期转移性疾病中，因此有理由采用早期免疫治疗方法。这些观察结果促使我们设计一种多价疫苗构建体，以便早期给予有高进展风险的黑色素瘤患者。为了比较可能的疫苗接种方案，我们将该构建体编码于几种不同载体中，并开发新型四聚体以追踪转基因小鼠对人类黑色素瘤表位的反应。用异源载体中编码的相同多表位构建体进行初次免疫和加强免疫，可导致具有单一显性特异性的CTL扩增。通过抗原呈递细胞将抗原分开进行独立呈递，可逆转免疫显性效应并诱导强大的多价CTL反应。这些结果为未来的疫苗接种试验提供了重要指导，而四聚体将成为这些临床研究免疫监测中的重要工具。
