High frequency of autologous anti-melanoma CTL directed against an antigen generated by a point mutation in a new helicase gene
High frequency of autologous anti-melanoma CTL directed against an antigen generated by a point mutation in a new helicase gene
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DOI：
10.4049/jimmunol.164.11.6057
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发表时间：
2000-06-01
影响因子：
4.4
通讯作者：
Coulie, PG
中科院分区：
文献类型：
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作者：
Baurain, JF;Colau, D;Coulie, PG
我们已经在一位患者的黑色素瘤细胞上发现了一种由自体CTL识别的抗原，该患者的临床演变异常良好。该抗原肽由人类白细胞抗原A28分子呈递，由一个新基因的突变序列编码。该基因被命名为MUM-3，广泛表达，与RNA解旋酶基因家族具有同源性。极限稀释分析表明，至少0.15%的血液CD8T细胞是肿瘤特异性CTL前体细胞。90%的CTL可识别MUM-3抗原，表明它是肿瘤特异性CTL反应的主要靶抗原。用负载抗原肽的四聚体可溶性HLA-A28分子证实了高频率的抗MUM-3CTL。MU-3四聚体对1.2%的血液CD8细胞进行染色，这一频率在针对严格的肿瘤特异性抗原的T细胞中从未报道过。为了证实这些结果，我们在克隆条件下对明显标记了四聚体的CDS T细胞进行了重新刺激。通过改进肿瘤细胞体外再刺激CTL前体的条件，在极限稀释度分析中可以获得相同的频率。这些结果表明，某些癌症患者有针对严格的肿瘤特异性抗原的高频率循环CTL，这些CTL在体外对再刺激有反应，并容易用四聚体检测，因此这种反应可能是肿瘤特异性AGS治疗性疫苗的一个可实现的目标。
We have identified an Ag recognized by autologous CTL on the melanoma cells of a patient who enjoyed an unusually favorable clinical evolution. The antigenic peptide, which is presented by HLA-A28 molecules, is encoded by a mutated sequence in a new gene. This gene, which was named MUM-3, is expressed ubiquitously and shows homology with the RNA helicase gene family. Limiting dilution analysis indicated that at least 0.15% of the blood CD8 T cells were tumor-specific CTL precursors. The MUM-3 Ag was recognized by 90% of these CTL, indicating that it is the dominant target Ag of the tumor-specific CTL response. The high frequency of anti-MUM-3 CTL was confirmed with tetramers of soluble HLA-A28 molecules loaded with the antigenic peptide. MUM-3 tetramers stained 1.2% of blood CD8 cells, a frequency that has never been reported for T cells directed against a strictly tumor-specific Ag, To confirm these results, the CDS T cells that were clearly labeled with tetramers were restimulated in clonal conditions. About 90% of these cells proliferated, and all the resulting clones proved lytic and MUM-3 specific, By improving the conditions used for the in vitro restimulation of CTL precursors by the tumor cells, the same frequency could be obtained in limiting dilution analysis. These results show that some cancer patients have a high frequency of circulating CTL that are directed against a strictly tumor-specific Ag, These CTL are responsive to restimulation in vitro and are easily detected with tetramers, Such responses may therefore be an achievable goal for therapeutic vaccination with tumor-specific Ags.