Tršan Tihana, Vuković Kristina, Filipović Petra, Brizić Ana Lesac, Lemmermann Niels A W, Schober Kilian, Busch Dirk H, Britt William J, Messerle Martin, Krmpotić Astrid, Jonjić Stipan
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Eur J Immunol. 2017 Aug;47(8):1354-1367. doi: 10.1002/eji.201746964. Epub 2017 Jul 4.
Designing CD8 T-cell vaccines, which would provide protection against tumors is still considered a great challenge in immunotherapy. Here we show the robust potential of cytomegalovirus (CMV) vector expressing the NKG2D ligand RAE-1γ as CD8 T cell-based vaccine against malignant tumors. Immunization with the CMV vector expressing RAE-1γ, delayed tumor growth or even provided complete protection against tumor challenge in both prophylactic and therapeutic settings. Moreover, a potent tumor control in mice vaccinated with this vector can be further enhanced by blocking the immune checkpoints TIGIT and PD-1. CMV vector expressing RAE-1γ potentiated expansion of KLRG1 CD8 T cells with enhanced effector properties. This vaccination was even more efficient in neonatal mice, resulting in the expansion and long-term maintenance of epitope-specific CD8 T cells conferring robust resistance against tumor challenge. Our data show that immunomodulation of CD8 T-cell responses promoted by herpesvirus expressing a ligand for NKG2D receptor can provide a powerful platform for the prevention and treatment of CD8 T-cell sensitive tumors.
设计能够提供肿瘤防护的CD8 T细胞疫苗在免疫疗法中仍然被认为是一项巨大挑战。在此，我们展示了表达NKG2D配体RAE-1γ的巨细胞病毒（CMV）载体作为基于CD8 T细胞的抗肿瘤疫苗的强大潜力。用表达RAE-1γ的CMV载体进行免疫接种，在预防和治疗环境中均延缓了肿瘤生长，甚至提供了完全的肿瘤攻击防护。此外，通过阻断免疫检查点TIGIT和PD-1，接种该载体的小鼠中的有效肿瘤控制可进一步增强。表达RAE-1γ的CMV载体增强了具有增强效应特性的KLRG1 CD8 T细胞的扩增。这种疫苗接种在新生小鼠中甚至更有效，导致表位特异性CD8 T细胞的扩增和长期维持，赋予对肿瘤攻击的强大抗性。我们的数据表明，由表达NKG2D受体配体的疱疹病毒促进的CD8 T细胞反应的免疫调节可为CD8 T细胞敏感肿瘤的预防和治疗提供一个强大的平台。
