Epitope spreading upon P815 tumor rejection triggered by vaccination with the single class I MHC-restricted peptide P1A
Epitope spreading upon P815 tumor rejection triggered by vaccination with the single class I MHC-restricted peptide P1A
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DOI：
10.1093/intimm/13.5.625
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发表时间：
2001-05-01
影响因子：
4.4
通讯作者：
Gajewski, TF
中科院分区：
文献类型：
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作者：
Markiewicz, MA;Fallarino, F;Gajewski, TF
表位扩展在CD4(+) T细胞依赖性自身免疫疾病模型中被很好地描述为一种加重因素，并且据信是通过由针对主要表位的CD4 + T细胞引发的组织破坏所释放的抗原的呈递而发生的。越来越多的证据表明外源性抗原也可由I类主要组织相容性复合体（MHC）分子加工和呈递，这提示在CD8(+)细胞毒性T淋巴细胞（CTL）应答中也可能发生表位扩展。在抗肿瘤免疫的背景下，CTL应答扩展至包括次要表位可能会提高治疗性疫苗的效力。为了直接确定在抗肿瘤免疫应答过程中是否会发生表位扩展，在P815肿瘤模型中使用了两种明确的I类MHC结合肽。我们观察到，用单一肿瘤肽P1A免疫，随后排斥P1A(+)肿瘤，随后产生了针对P1A(-)肿瘤变体的CTL活性和肿瘤保护作用。用P1A免疫且随后排斥肿瘤攻击的小鼠产生了针对第二个明确表位P1E的CTL。这些结果表明，如同自身免疫疾病中II类限制性肽一样，在肿瘤排斥过程中针对I类限制性肽也可能发生表位扩展。广泛的CTL应答可能有助于消除抗原阴性肿瘤变体的生长。
Epitope spreading has been best characterized as an exacerbating factor in CD4(+) T cell-dependent autoimmune disease models and is believed to occur via presentation of antigens liberated by tissue destruction initiated by CD4+ T cells specific for a primary epitope, The growing evidence that exogenous antigens can also be processed and presented by class I MHC molecules has suggested that epitope spreading could occur for CD8(+) cytotoxic T lymphocyte (CTL) responses as well, In the context of anti-tumor immunity, expansion of a CTL response to include secondary epitopes could improve the efficacy of therapeutic vaccines, To determine directly whether epitope spreading can occur during an anti-tumor immune response, two defined class I MHC-binding peptides in the P815 tumor model were utilized. We observed that immunization against the single tumor peptide, P1A, followed by rejection of a P1A(+) tumor, subsequently yielded CTL activity and tumor protection against a P1A(-) tumor variant, P1A immunized mice that subsequently rejected tumor challenge developed CTL against a second defined epitope, P1E. These results indicate that, as for class II-restricted peptides in autoimmune disease, epitope spreading can occur for class II-restricted peptides during tumor rejection. A broadened CT response may help eliminate outgrowth of antigen-negative tumor variants.