Identification of a lung cancer antigen evading CTL attack due to loss of human leukocyte antigen (HLA) class I expression
Identification of a lung cancer antigen evading CTL attack due to loss of human leukocyte antigen (HLA) class I expression
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DOI：
10.1111/j.1349-7006.2010.01659.x
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发表时间：
2010-10
期刊：
影响因子：
5.7
通讯作者：
T. Baba;T. Hanagiri;M. Takenoyama;Hironobu Shiota;K. Kuroda;Y. Shigematsu;Y. Ichiki;H. Uramoto;T. So;K. Yasumoto
中科院分区：
文献类型：
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作者：
T. Baba;T. Hanagiri;M. Takenoyama;Hironobu Shiota;K. Kuroda;Y. Shigematsu;Y. Ichiki;H. Uramoto;T. So;K. Yasumoto
人肺癌细胞系C831 L由于β2微球蛋白（β 2 m）基因突变而失去HLA I类表达，这可能是CTL细胞毒性免疫编辑的结果。通过恢复HLA I类表达，我们可以鉴定可能与HLA下调相关的抗原。这种抗原可能是免疫治疗的一个有希望的靶点，因为它可能诱导足够的免疫应答以根除癌细胞。通过用野生型β 2 m-转导的C831 L（C831 L-w β 2 m）刺激，可以从患者C831的淋巴结淋巴细胞中建立CTL克隆。CTL克隆以HLA-B*0702-限制性方式显示出对C831 L-wβ 2 m的反应性，但不显示亲本-C831 L或自体正常细胞的反应性。用cDNA表达克隆法鉴定CTL克隆识别的抗原编码基因。该cDNA克隆与编码富含亮氨酸重复序列的八个家族成员A（LRRC 8A）的部分mRNA具有同源性。小基因的转染分析表明，抗原肽来源于从LRRC 8A mRNA中注册的开放阅读框的下游翻译的蛋白质。鉴定了抗原性9聚体肽（GPRESRPPA）。目前的方法应该是有用的，以找到关键的肿瘤抗原，这是潜在的与HLA表达的损失。此外，这种抗原可能有助于更好地了解免疫逃逸机制，并且还可能在癌症免疫治疗中提供有利的免疫反应。（Cancer Sci 2010; 00：000-000）
The human lung cancer cell line, C831L, lost HLA class I expression due to a mutation of the β2‐microglobulin (β2m) gene, and it may have been the result of immunoediting by CTL cytotoxicity. By restoration of HLA class I expression, we could identify the antigen that may be associated with HLA downregulation. Such an antigen might be a promising target of immunotherapy because it potentially may induce a sufficient immune response to eradicate cancer cells. The CTL clone could be established from lymph node lymphocytes in patient C831 by stimulation with wild‐type β2m‐transduced C831L (C831L‐wβ2m). The CTL clone showed reactivity against C831L‐wβ2m in a HLA‐B*0702‐restricted manner, but not Parental‐C831L or autologous normal cells. The cDNA expression cloning method was used to identify the antigen coding gene recognized by the CTL clone. The cDNA clone exhibited a homology with a part of the mRNA that codes for leucine rich repeat containing eight family member A (LRRC8A). A transfection analysis of minigenes indicated that the antigen peptide was derived from protein translated from the downstream of the registered open reading frame in LRRC8A mRNA. The antigenic 9‐mer peptide (GPRESRPPA) was identified. The present methodology should be useful to find the crucial tumor antigens, which are potentially associated with loss of HLA expression. Furthermore, such an antigen may help in achieving a better understanding of the immunological escape mechanisms and it may also provide a favorable immune response in cancer immunotherapy. (Cancer Sci 2010; 00: 000–000)