ABSTRACT

Simulating a viral infection in tumor cells is an attractive concept to eliminate tumor cells. We previously reported the molecular design and the in vitro potency of recombinant monoclonal antibodies fused to a virus-derived peptide MHC class I complex that bypass the peptide processing and MHC loading pathway and directly displays a viral peptide in an MHC class I complex on the tumor cell surface. Here, we show that a vaccination-induced single peptide-specific CD8 T cell response was sufficient to eliminate B16 melanoma tumor cells in vivo in a fully immunocompetent, syngeneic mouse tumor model when mice were treated with mouse pMHCI-IgGs fusion proteins targeting the mouse fibroblast activation protein. Tumor growth of small, established B16 lung metastases could be controlled. The pMHCI-IgG had similar potency as an analogous pan-CD3 T-cell bispecific antibody. In contrast to growth control of small tumors, none of the compounds controlled larger solid tumors of MC38 cancer cells, despite penetration of pMHCI-IgGs into the tumor tissue and clear attraction and activation of antigen-specific CD8 T cells inside the tumor. pMHCI-IgG can have a similar potency as classical pan-T-cell recruiting molecules. The results also highlight the need to better understand immune suppression in advanced solid tumors.

 抽象的

模拟肿瘤细胞中的病毒感染是消除肿瘤细胞的一个有吸引力的概念。我们之前报道了与病毒衍生肽 MHC I 类复合物融合的重组单克隆抗体的分子设计和体外效力，该抗体绕过肽加工和 MHC 加载途径，直接在肿瘤上展示 MHC I 类复合物中的病毒肽细胞表面。在这里，我们表明，当用靶向小鼠的小鼠 pMHCI-IgG 融合蛋白治疗小鼠时，疫苗接种诱导的单肽特异性 CD8 T 细胞反应足以在完全免疫活性的同基因小鼠肿瘤模型中消除体内 B16 黑色素瘤肿瘤细胞成纤维细胞激活蛋白。已形成的小型 B16 肺转移瘤的肿瘤生长可以得到控制。 pMHCI-IgG 与类似的泛 CD3 T 细胞双特异性抗体具有相似的效力。与小肿瘤的生长控制相反，尽管 pMHCI-IgG 渗透到肿瘤组织中并且明显吸引和激活肿瘤内的抗原特异性 CD8 T 细胞，但没有一种化合物能够控制 MC38 癌细胞的较大实体瘤。 pMHCI-IgG 可以具有与经典泛 T 细胞招募分子相似的效力。结果还强调需要更好地了解晚期实体瘤中的免疫抑制。