Cytotoxic T lymphocyte (CTL)-mediated immune responses are the primary defense mechanism against cancer and infection. CTL epitope peptides have been used as vaccines to boost CTL responses; however, the efficacy of these peptides is suboptimal. Under current vaccine formulation and delivery strategies, these vaccines are delivered into and processed inside antigen-presenting cells such as dendritic cells (DCs). However, the intracellular process is not efficient, which at least partially contributes to the suboptimal efficacy of the vaccines. Thus, we hypothesized that directly loading epitopes onto MHC class I complexes (MHC-Is) on the DC surface would significantly improve the efficacy of the epitopes because the direct loading bypasses inefficient intra-DC vaccine processing. To test the hypothesis, we designed an immune-tolerant elastin-like polypeptide (iTEP)-delivered CTL vaccine containing a metalloproteinase-9 (MMP-9)-sensitive peptide and an CTL epitope peptide. We found that the epitope was released from this MMP-sensitive vaccine through cleavage by DC-secreted MMP-9 outside of the DCs. The released epitopes were directly loaded onto MHC-Is on the DC surface. Ultimately, the MMP-sensitive vaccine strikingly increased epitope presentation by DCs by 7-fold and enhanced the epitope-specific CD8+ T-cell response by as high as 9.6-fold compared to the vaccine that was uncleavable by MMP. In summary, this novel direct-loading strategy drastically boosted vaccine efficacy. This study offered a new avenue to enhance CTL vaccines.

中文翻译：

---

将iTEP传递的CTL表位直接加载到树突状细胞表面的MHC I类复合物上

细胞毒性T淋巴细胞（CTL）介导的免疫反应是抵抗癌症和感染的主要防御机制。CTL表位肽已被用作增强CTL反应的疫苗。然而，这些肽的功效欠佳。在当前的疫苗配制和递送策略下，这些疫苗被递送到抗原呈递细胞例如树突细胞（DC）中并在其内部加工。然而，细胞内过程不是有效的，这至少部分地导致了疫苗的次优功效。因此，我们假设将表位直接加载到DC表面的MHC I类复合物（MHC-Is）上将显着提高表位的功效，因为直接加载绕过了低效的DC内疫苗处理。为了检验假设，我们设计了一种包含金属蛋白酶9（MMP-9）敏感肽和CTL表位肽的免疫耐受弹性蛋白样多肽（iTEP）提供的CTL疫苗。我们发现，抗原表位是通过DC外部DC分泌的MMP-9的切割而从这种MMP敏感疫苗中释放出来的。释放的表位直接加载到DC表面的MHC-Is上。最终，与MMP无法裂解的疫苗相比，MMP敏感疫苗显着地将DC的抗原决定簇呈递提高了7倍，并将抗原决定簇特异性CD8 + T细胞应答提高了9.6倍。总而言之，这种新颖的直接加载策略极大地提高了疫苗效力。这项研究提供了增强CTL疫苗的新途径。