Dutoit V, Rubio-Godoy V, Dietrich P Y, Quiqueres A L, Schnuriger V, Rimoldi D, Liénard D, Speiser D, Guillaume P, Batard P, Cerottini J C, Romero P, Valmori D
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Centre Hospitalier Universitaire Vaudois, Avenue Pierre-Decker, 1011 Lausanne, Switzerland.
Cancer Res. 2001 Aug 1;61(15):5850-6.
MAGE-encoded antigens, which are expressed by tumors of many histological types but not in normal tissues, are suitable candidates for vaccine-based immunotherapy of cancers. Thus far, however, T-cell responses to MAGE antigens have been detected only occasionally in cancer patients. In contrast, by using HLA/peptide fluorescent tetramers, we have observed recently that CD8(+) T cells specific for peptide MAGE-A10(254-262) can be detected frequently in peptide-stimulated peripheral blood mononuclear cells from HLA-A2-expressing melanoma patients and healthy donors. On the basis of these results, antitumoral vaccination trials using peptide MAGE-A10(254-262) have been implemented recently. In the present study, we have characterized MAGE-A10(254-262)-specific CD8(+) T cells in polyclonal cultures and at the clonal level. The results indicate that the repertoire of MAGE-A10(254-262)-specific CD8(+) T cells is diverse both in terms of clonal composition, efficiency of peptide recognition, and tumor-specific lytic activity. Importantly, only CD8(+) T cells able to recognize the antigenic peptide with high efficiency are able to lyse MAGE-A10-expressing tumor cells. Under defined experimental conditions, the tetramer staining intensity exhibited by MAGE-A10(254-262)-specific CD8(+) T cells correlates with efficiency of peptide recognition so that "high" and "low" avidity cells can be separated by FACS. Altogether, the data reported here provide evidence for functional diversity of MAGE-A10(254-262)-specific T cells and will be instrumental for the monitoring of peptide MAGE-A10(254-262)-based clinical trials.
黑色素瘤相关抗原（MAGE）编码的抗原可由多种组织学类型的肿瘤表达，但正常组织中不表达，是基于疫苗的癌症免疫疗法的合适候选对象。然而，迄今为止，仅在癌症患者中偶尔检测到针对MAGE抗原的T细胞反应。相比之下，通过使用HLA/肽荧光四聚体，我们最近观察到，在来自表达HLA-A2的黑色素瘤患者和健康供体的肽刺激外周血单个核细胞中，可频繁检测到对肽MAGE-A10（254-262）特异的CD8（+）T细胞。基于这些结果，最近开展了使用肽MAGE-A10（254-262）的抗肿瘤疫苗试验。在本研究中，我们在多克隆培养物和克隆水平上对MAGE-A10（254-262）特异的CD8（+）T细胞进行了特性分析。结果表明，MAGE-A10（254-262）特异的CD8（+）T细胞库在克隆组成、肽识别效率和肿瘤特异性裂解活性方面均具有多样性。重要的是，只有能够高效识别抗原肽的CD8（+）T细胞才能裂解表达MAGE-A10的肿瘤细胞。在特定实验条件下，MAGE-A10（254-262）特异的CD8（+）T细胞呈现的四聚体染色强度与肽识别效率相关，因此“高”亲和力和“低”亲和力细胞可通过荧光激活细胞分选术（FACS）分离。总之，本文报道的数据为MAGE-A10（254-262）特异T细胞的功能多样性提供了证据，并将有助于监测基于肽MAGE-A10（254-262）的临床试验。
