Valmori Danila, Lévy Frédéric, Godefroy Emmanuelle, Scotto Luigi, Souleimanian Naira E, Karbach Julia, Tosello Valeria, Hesdorffer Charles S, Old Lloyd J, Jager Elke, Ayyoub Maha
Ludwig Institute Clinical Trial Center, Department of Medicine, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building Room 20-09, New York, NY 10032, USA.
Clin Immunol. 2007 Feb;122(2):163-72. doi: 10.1016/j.clim.2006.09.005. Epub 2006 Oct 24.
Identification of immunodominant CD8(+) T cell responses to frequently expressed tumor antigens across MHC class I polymorphism is essential for the implementation of cancer immunotherapy. However, the key factors that determine immunodominance are not fully understood. Because of its frequent expression in tumors and its spontaneous immunogenicity, NY-ESO-1 is a prime target of cancer vaccines and an ideal model antigen for elucidating the molecular basis of immunodominant tumor-specific CD8(+) T cell responses. Here, we have assessed CD8(+)T cell responses to full-length NY-ESO-1 in cancer patients. We identified 3 immunodominant regions of the protein located within 3 distinct clusters of MHC class I binding sequences that co-localize with previously defined clusters of MHC class II binding sequences, are predicted to be hydrophobic and undergo efficient proteasomal processing. Our results support the concept that epitope clustering within defined protein regions identifies tumor antigen immunodominant regions and suggest a general strategy for their identification.
识别针对跨MHC I类多态性频繁表达的肿瘤抗原的免疫显性CD8(+) T细胞反应对于癌症免疫治疗的实施至关重要。然而，决定免疫显性的关键因素尚未完全明确。由于NY-ESO-1在肿瘤中频繁表达且具有自发免疫原性，它是癌症疫苗的主要靶点，也是阐明免疫显性肿瘤特异性CD8(+) T细胞反应分子基础的理想模型抗原。在此，我们评估了癌症患者中CD8(+) T细胞对全长NY-ESO-1的反应。我们确定了该蛋白的3个免疫显性区域，它们位于MHC I类结合序列的3个不同簇内，这些簇与先前定义的MHC II类结合序列簇共定位，预计具有疏水性并经历高效的蛋白酶体加工。我们的结果支持这样的概念，即特定蛋白区域内的表位聚类可识别肿瘤抗原免疫显性区域，并提出了识别它们的一般策略。
