Department of Oncology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15187-92. doi: 10.1073/pnas.1002155107. Epub 2010 Aug 9.
Cancer/testis (CT) antigens represent prime candidates for immunotherapy in cancer patients, because their expression is restricted to cancer cells and germ cells of the testis. MAGE-C1/CT7 is a CT antigen that is highly expressed in several types of cancers. Spontaneous occurrence of CT7-specific antibodies was previously detected by SEREX screen in a melanoma patient. However, naturally occurring CT7-specific T-cell responses have thus far not been detected. Peripheral blood mononuclear cells (PBMCs) from 26 metastatic melanoma patients expressing CT7 in their tumor lesions (CT7(+)) were analyzed for CT7-specific T-cell responses using overlapping peptides. CT7-specific CD4(+) T-cell responses were detected in three patients (11.5%). These CT7-specific CD4(+) T-cell responses were detectable in melanoma patients' PBMCs exclusively from preexisting CD45RA(-) memory CD4(+) T-cell pool. Additional CT7-specific memory CD4(+) T-cell responses were detected in CT7(+) melanoma patients after depletion of CD4(+)CD25high Treg cells showing that Treg cells impact on CT7-specific CD4(+) T cells in melanoma patients. CT7-specific CD4(+) T-cell clones were generated and used to define minimal epitopes, restriction elements, and confirm the recognition of naturally processed antigen. Surprisingly, these clones were able to secrete perforin and exert cytotoxicity. This study shows that CT7 can induce specific cellular immunity in melanoma patients. Based on these findings, CT7 will be further explored as a potential vaccine for melanoma immunotherapy.
癌症/睾丸（CT）抗原是癌症患者免疫治疗的主要候选者，因为它们的表达仅限于癌细胞和睾丸的生殖细胞。MAGE-C1/CT7 是一种 CT 抗原，在几种类型的癌症中高度表达。先前在黑色素瘤患者的 SEREX 筛选中检测到 CT7 特异性抗体的自发发生。然而，迄今为止尚未检测到自然发生的 CT7 特异性 T 细胞反应。分析了 26 名转移性黑色素瘤患者的外周血单核细胞（PBMC），这些患者的肿瘤病变中表达 CT7（CT7(+）），使用重叠肽分析 CT7 特异性 T 细胞反应。在三名患者（11.5%）中检测到 CT7 特异性 CD4(+) T 细胞反应。这些 CT7 特异性 CD4(+) T 细胞反应仅可从黑色素瘤患者的 PBMC 中预先存在的 CD45RA(-)记忆 CD4(+) T 细胞池中检测到。在耗尽 CD4(+)CD25high Treg 细胞后，在 CT7(+)黑色素瘤患者中检测到额外的 CT7 特异性记忆 CD4(+) T 细胞反应，表明 Treg 细胞对黑色素瘤患者的 CT7 特异性 CD4(+) T 细胞有影响。生成了 CT7 特异性 CD4(+) T 细胞克隆，并用于定义最小表位、限制元件，并确认对天然加工抗原的识别。令人惊讶的是，这些克隆能够分泌穿孔素并发挥细胞毒性作用。这项研究表明 CT7 可以在黑色素瘤患者中诱导特异性细胞免疫。基于这些发现，CT7 将进一步探索作为黑色素瘤免疫治疗的潜在疫苗。
