Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines
Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines
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DOI：
10.1172/jci26936
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发表时间：
2006-09-01
影响因子：
15.9
通讯作者：
Slansky, Jill E.
中科院分区：
文献类型：
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作者：
McMahan, Rachel H.;McWilliams, Jennifer A.;Slansky, Jill E.
增强 T 细胞对肿瘤反应的一种方法是接种模拟表位（模拟肿瘤表位）。虽然模拟表位可以刺激识别肿瘤相关抗原 (TAA) 的 T 细胞增殖，但这种增殖并不总是与肿瘤生长的控制相关。我们假设在这种相互作用中用具有最佳亲和力的模拟表位进行疫苗接种将提高抗肿瘤免疫力。使用组合肽库和识别 TAA 的细胞毒性 T 淋巴细胞克隆，我们鉴定了一组模拟表位，当与 MHC 复合时，它们以一系列亲和力结合 TAA 特异性 TCR。正如预期的那样，体外测定表明 TCR-肽-MHC (TCR-pMHC) 相互作用的亲和力与 T 细胞克隆的活性相关。然而，只有用中等亲和力范围内的模拟表位进行疫苗接种才能激发功能性 T 细胞并提供针对体内肿瘤生长的保护。使用具有最高亲和力的 TCR-pMHC 相互作用的模拟表位进行疫苗接种可引发肿瘤 TAA 特异性 T 细胞，但在任何测试的肽浓度下都不能控制肿瘤生长。对这些 T 细胞的进一步分析显示出对 TAA 反应的功能缺陷。因此，通过模拟表位刺激抗肿瘤反应可能是最佳的，使用增加但不最大化TCR-pMHC相互作用的亲和力的肽。
One approach to enhancing the T cell response to tumors is vaccination with mimotopes, mimics of tumor epitopes. While mimotopes can stimulate proliferation of T cells that recognize tumor-associated antigens (TAAs), this expansion does not always correlate with control of tumor growth. We hypothesized that vaccination with mimotopes of optimal affinity in this interaction will improve antitumor immunity. Using a combinatorial peptide library and a cytotoxic T lymphocyte clone that recognizes a TAA, we identified a panel of mimotopes that, when complexed with MHC, bound the TAA-specific TCR with a range of affinities. As expected, in vitro assays showed that the affinity of the TCR-peptide-MHC (TCR-pMHC) interaction correlated with activity of the T cell clone. However, only vaccination with mimotopes in the intermediate-affinity range elicited functional T cells and provided protection against tumor growth in vivo. Vaccination with mimotopes with the highest-affinity TCR-pMHC interactions elicited TAA-specific T cells to the tumor, but did not control tumor growth at any of the peptide concentrations tested. Further analysis of these T cells showed functional defects in response to the TAA. Thus, stimulation of an antitumor response by mimotopes may be optimal with peptides that increase but do not maximize the affinity of the TCR-pMHC interaction.