Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex
Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex
复制标题
DOI：
10.1016/s1074-7613(00)00052-2
复制
发表时间：
2000-10-01
期刊：
影响因子：
32.4
通讯作者：
Pardoll, DM
中科院分区：
文献类型：
--
作者：
Slansky, JE;Rattis, FM;Pardoll, DM
T细胞对一个表位的反应性既受其与呈递MHC分子的亲和力影响，也受MHC - 肽复合物对TCR的亲和力影响。癌症免疫疗法的一个局限在于，天然肿瘤抗原引发的T细胞反应相对较弱，部分原因是高亲和力的T细胞对这些抗原产生了耐受性。我们在此报道，在一种天然的MHC I类限制性肿瘤抗原中进行氨基酸替换，可增加MHC - 肽 - TCR复合物的稳定性，其作为肿瘤疫苗的效力显著增强。免疫增强是由于天然肿瘤表位特异性T细胞在体内的扩增增强。这些结果表明，稳定MHC - 肽 - TCR复合物的肽段可通过增强对特异性T细胞的刺激而提供更强的抗肿瘤免疫力。
T cell responsiveness to an epitope is affected both by its affinity for the presenting MHC molecule and the affinity of the MHC-peptide complex for TCR. One limitation of cancer immunotherapy is that natural tumor antigens elicit relatively weak T cell responses, in part because high-affinity T cells are rendered tolerant to these antigens. We report here that amino acid substitutions in a natural MHC class I-restricted tumor antigen that increase the stability of the MHC-peptide-TCR complex are significantly more potent as tumor vaccines. The improved immunity results from enhanced in vivo expansion of T cells specific for the natural tumor epitope. These results indicate peptides that stabilize the MHC-peptide-TCR complex may provide superior antitumor immunity through enhanced stimulation of specific T cells.