Jäger E, Ringhoffer M, Altmannsberger M, Arand M, Karbach J, Jäger D, Oesch F, Knuth A
Medical Clinic, Hematology/Oncology, Nordwest Hospital, Frankfurt am Main, Germany.
Int J Cancer. 1997 Apr 10;71(2):142-7. doi: 10.1002/(sici)1097-0215(19970410)71:2<142::aid-ijc3>3.0.co;2-0.
Peptides derived from melanocyte differentiation antigens have been identified as targets for MHC class I-restricted cytolytic T lymphocytes (CTLs) in human melanoma Regression of antigen-expressing tumors as well as selection of antigen-loss variants in the presence of antigen-specific CTLs have previously been reported. In the present study, we determined the expression of the melanocyte differentiation antigens Melan A/MART-1 and tyrosinase by mRNA analysis and by immunohistochemical staining with the monoclonal antibodies (MAbs) A103 and T311. Co-expression of Melan A/MART-1 and tyrosinase was detected by both methods in 18/20 melanomas tested. However, immunohistochemistry provided additional information on intensity and microheterogeneity of antigen expression that cannot be detected by mRNA analysis as a molecular basis for the escape from CTL recognition of antigen-negative tumor cells. Comparative analysis of repeated biopsies of metastatic lesions in 5 HLA-A2+ patients showed a gradual loss of Melan A/MART-1 expression in 4/5 and of tyrosinase in 2/5 samples in association with tumor progression. However, 3 of these patients had growing antigen-positive tumors in the presence of antigen-specific CTLs. This led us to assess the expression of MHC class I, the essential restriction element for CTL recognition, and of HLA-A2. We found an unexpectedly high frequency of MHC class I-negative tumors (9/20). Loss of MHC class I expression was detected in 3/5 progressive tumors and isolated loss of HLA-A2 in 1/5 tumors. Our results suggest that strategies enhancing the expression of MHC class I and tumor-associated antigens need to be considered in attempts at making vaccination more effective.
源自黑素细胞分化抗原的肽已被确定为人类黑色素瘤中MHC I类限制性细胞毒性T淋巴细胞（CTL）的靶标。先前已有报道称，表达抗原的肿瘤会消退，以及在存在抗原特异性CTL的情况下会选择抗原缺失变体。在本研究中，我们通过mRNA分析以及使用单克隆抗体（MAb）A103和T311进行免疫组织化学染色，来确定黑素细胞分化抗原Melan A/MART-1和酪氨酸酶的表达。在检测的20例黑色素瘤中有18例通过这两种方法均检测到Melan A/MART-1和酪氨酸酶的共表达。然而，免疫组织化学提供了关于抗原表达强度和微异质性的额外信息，而mRNA分析作为抗原阴性肿瘤细胞逃避CTL识别的分子基础无法检测到这些信息。对5例HLA-A2+患者转移性病变的重复活检进行比较分析显示，随着肿瘤进展，4/5的样本中Melan A/MART-1表达逐渐丧失，2/5的样本中酪氨酸酶表达逐渐丧失。然而，其中3例患者在存在抗原特异性CTL的情况下有生长的抗原阳性肿瘤。这促使我们评估CTL识别的关键限制元件MHC I类以及HLA-A2的表达。我们发现MHC I类阴性肿瘤的频率出乎意料地高（9/20）。在3/5的进展性肿瘤中检测到MHC I类表达缺失，在1/5的肿瘤中检测到HLA-A2的孤立缺失。我们的结果表明，在试图提高疫苗接种效果时，需要考虑增强MHC I类和肿瘤相关抗原表达的策略。
