Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
J Immunol. 2011 Jan 1;186(1):312-22. doi: 10.4049/jimmunol.1001989. Epub 2010 Dec 3.
NY-ESO-1 and LAGE-1 represent highly homologous cancer-germline Ags frequently coexpressed by many human cancers, but not by normal tissues, except testis. In contrast to NY-ESO-1, little is known about spontaneous immune responses to LAGE-1. In the current study, we report on spontaneous LAGE-1-specific CD4(+) T cells isolated from PBLs of patients with advanced LAGE-1(+)/NY-ESO-1(+) melanoma and directed against three promiscuous and immunodominant epitopes. Strikingly, although the three LAGE-1-derived epitopes are highly homologous to NY-ESO-1-derived epitopes, LAGE-1-specific CD4(+) T cells did not cross-react with NY-ESO-1. LAGE-1-specific CD4(+) T cells produced Th1-type and/or Th2-type cytokines and did not exert inhibitory effects on allogenic T cells. We observed that most patients with spontaneous NY-ESO-1-specific responses exhibited spontaneous CD4(+) T cell responses to at least one of the three immunodominant LAGE-1 epitopes. Additionally, nearly half of the patients with spontaneous LAGE-1-specific CD4(+) T cell responses had circulating LAGE-1-specific Abs that recognized epitopes located in the C-terminal portion of LAGE-1, which is distinct from NY-ESO-1. Collectively, our findings define the hierarchy of immunodominance of spontaneous LAGE-1-specific CD4(+) T cell responses in patients with advanced melanoma. These findings demonstrate the capability of LAGE-1 to stimulate integrated cellular and humoral immune responses that do not cross-react with NY-ESO-1. Therefore, they provide a strong rationale for the inclusion of LAGE-1 peptides or protein in vaccine trials for patients with NY-ESO-1(+)/LAGE-1(+) tumors.
NY-ESO-1 和 LAGE-1 代表高度同源的癌症-种系抗原，经常由许多人类癌症共同表达，但除睾丸外，正常组织不表达。与 NY-ESO-1 不同，人们对 LAGE-1 的自发免疫反应知之甚少。在目前的研究中，我们报告了从晚期 LAGE-1(+)/NY-ESO-1(+)黑色素瘤患者的 PBL 中分离出的针对三个混杂和免疫优势表位的自发 LAGE-1 特异性 CD4(+) T 细胞。引人注目的是，尽管这三个 LAGE-1 衍生的表位与 NY-ESO-1 衍生的表位高度同源，但 LAGE-1 特异性 CD4(+) T 细胞不会与 NY-ESO-1 发生交叉反应。LAGE-1 特异性 CD4(+) T 细胞产生 Th1 型和/或 Th2 型细胞因子，对同种异体 T 细胞没有抑制作用。我们观察到，大多数具有自发 NY-ESO-1 特异性反应的患者至少对三个免疫优势 LAGE-1 表位中的一个表现出自发的 CD4(+) T 细胞反应。此外，近一半具有自发 LAGE-1 特异性 CD4(+) T 细胞反应的患者具有循环 LAGE-1 特异性 Ab，这些 Ab 识别位于 LAGE-1 C 端部分的表位，这与 NY-ESO-1 不同。总之，我们的研究结果定义了晚期黑色素瘤患者中自发 LAGE-1 特异性 CD4(+) T 细胞反应的免疫优势层次。这些发现表明 LAGE-1 能够刺激不与 NY-ESO-1 发生交叉反应的整合细胞和体液免疫反应。因此，它们为在 NY-ESO-1(+)/LAGE-1(+) 肿瘤患者的疫苗试验中纳入 LAGE-1 肽或蛋白提供了强有力的依据。
