Palermo B, Campanelli R, Garbelli S, Mantovani S, Robustelli Della Cuna G, Necker A, Manganoni A M, Carella G, Rivoltini L, Lantelme E, Giachino C
Experimental Immunology, IRCCS Maugeri Foundation, Pavia, Italy.
Melanoma Res. 2002 Oct;12(5):491-8. doi: 10.1097/00008390-200209000-00011.
Modifications in tumour antigen-derived epitopes that stabilize the major histocompatibility complex (MHC)-peptide complex result in enhanced stimulatory capacity and improved immunogenicity of the altered peptide. These epitope analogues are attractive candidates for the development of peptide-based vaccine trials. Any modification, however, in tumour antigens may induce T-cell responses that could either fail to react against the naturally occurring peptides or represent only a subset of the total antigen-specific repertoire. In the present study, we performed a critical analysis of the ability of cytotoxic T-lymphocyte (CTL) clones, derived from two melanoma patients through stimulation with the A27L peptide analogue, to cross-react with the naturally processed Melan-A/MART-1 (Melan-A) peptides in terms of T-cell receptor (TCR) affinity, functional avidity and fine antigen specificity. We found that all the A27L-specific clones analysed possessed a very low avidity for the natural Melan-A peptides, and that their binding affinity for human leukocyte antigen (HLA) tetramers complexed with both the modified and the natural Melan-A peptides did not strictly correlate with their functional avidity. We also observed that these clones were able to cross-recognize both natural Melan-A peptides in one patient, but only one peptide in the second patient. We discuss the capability of the A27L peptide analogue to stimulate all the available Melan-A-specific repertoire.
对肿瘤抗原衍生表位进行修饰，使主要组织相容性复合体（MHC）-肽复合物稳定，可增强修饰肽的刺激能力并改善其免疫原性。这些表位类似物是基于肽的疫苗试验开发的有吸引力的候选物。然而，肿瘤抗原的任何修饰都可能诱导T细胞反应，这种反应可能无法对天然存在的肽产生反应，或者仅代表总抗原特异性库的一个子集。在本研究中，我们对通过用A27L肽类似物刺激从两名黑色素瘤患者获得的细胞毒性T淋巴细胞（CTL）克隆与天然加工的黑色素瘤抗原A/MART-1（Melan-A）肽发生交叉反应的能力进行了批判性分析，分析内容涉及T细胞受体（TCR）亲和力、功能亲和力和精细抗原特异性。我们发现，所有分析的A27L特异性克隆对天然Melan-A肽的亲和力都非常低，并且它们与修饰和天然Melan-A肽复合的人白细胞抗原（HLA）四聚体的结合亲和力与其功能亲和力并不严格相关。我们还观察到，这些克隆能够交叉识别一名患者中的两种天然Melan-A肽，但在另一名患者中只能识别一种肽。我们讨论了A27L肽类似物刺激所有可用的Melan-A特异性库的能力。
