Topalian Suzanne L, Gonzales Monica I, Ward Yvona, Wang Xiang, Wang Rong-Fu
Surgery Branch, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland 20892-1502, USA.
Cancer Res. 2002 Oct 1;62(19):5505-9.
CD4+ T-cell responses against human tumor antigens are a potentially critical component of the antitumor immune response. Molecular methods have been devised for rapidly identifying MHC class II-restricted tumor antigens and elucidating the recognized epitopes. We describe here the identification of neo-poly(A) polymerase (neo-PAP), a novel RNA processing enzyme overexpressed in a variety of human cancers, by screening a melanoma-derived invariant chain fusion cDNA library with tumor-reactive CD4+ T lymphocytes. A cryptic nonmutated HLA-DRbeta1*0701-restricted neo-PAP epitope was processed through the endogenous MHC class II pathway. A unique point mutation effected a nonconservative substitution of a leucine for a proline residue at a structurally important site in neo-PAP that was remote from the recognized peptide, revealing a normally silent epitope for immune recognition. Genetic aberrations such as the described point mutation can have unexpected immunological consequences, in this case leading to immune recognition of a distant normal self epitope.
针对人类肿瘤抗原的CD4 + T细胞反应是抗肿瘤免疫反应的一个潜在关键组成部分。已经设计出分子方法用于快速鉴定II类主要组织相容性复合体（MHC）限制的肿瘤抗原并阐明被识别的表位。我们在此描述了通过用肿瘤反应性CD4 + T淋巴细胞筛选黑色素瘤衍生的恒定链融合cDNA文库来鉴定新聚（A）聚合酶（neo-PAP），这是一种在多种人类癌症中过表达的新型RNA加工酶。一个隐蔽的未突变的HLA-DRβ1* 0701限制的neo-PAP表位通过内源性II类MHC途径进行加工。一个独特的点突变在neo-PAP中一个远离被识别肽段的结构重要位点导致脯氨酸残基被亮氨酸非保守取代，从而揭示了一个正常情况下沉默的可被免疫识别的表位。诸如所描述的点突变这样的基因畸变可能会产生意想不到的免疫学后果，在这种情况下导致对远处正常自身表位的免疫识别。
