Britsch Isabel, van Wijngaarden Anne Paulien, Helfrich Wijnand
Department of Surgery, Translational Surgical Oncology, University of Groningen, UMC Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Cancers (Basel). 2023 Jul 25;15(15):3767. doi: 10.3390/cancers15153767.
Infection with cytomegalovirus (CMV) is highly prevalent in the general population and largely controlled by CD8 T cells. Intriguingly, anti-CMV T cells accumulate over time to extraordinarily high numbers, are frequently present as tumor-resident 'bystander' T cells, and remain functional in cancer patients. Consequently, various strategies for redirecting anti-CMV CD8 T cells to eliminate cancer cells are currently being developed. Here, we provide an overview of these strategies including immunogenic CMV peptide-loading onto endogenous HLA complexes on cancer cells and the use of tumor-directed fusion proteins containing a preassembled CMV peptide/HLA-I complex. Additionally, we discuss conveying the advantageous characteristics of anti-CMV T cells in adoptive cell therapy. Utilization of anti-CMV CD8 T cells to generate CAR T cells promotes their in vivo persistence and expansion due to appropriate co-stimulation through the endogenous (CMV-)TCR signaling complex. Designing TCR-engineered T cells is more challenging, as the artificial and endogenous TCR compete for expression. Moreover, the use of expanded/reactivated anti-CMV T cells to target CMV peptide-expressing glioblastomas is discussed. This review highlights the most important findings and compares the benefits, disadvantages, and challenges of each strategy. Finally, we discuss how anti-CMV T cell therapies can be further improved to enhance treatment efficacy.
巨细胞病毒（CMV）感染在普通人群中极为普遍，且在很大程度上由CD8 T细胞控制。有趣的是，抗CMV T细胞会随着时间的推移积累到极高的数量，经常作为肿瘤驻留的“旁观者”T细胞存在，并在癌症患者中保持功能。因此，目前正在开发各种将抗CMV CD8 T细胞重定向以消除癌细胞的策略。在此，我们概述了这些策略，包括将免疫原性CMV肽加载到癌细胞上的内源性HLA复合物上，以及使用含有预组装的CMV肽/HLA-I复合物的肿瘤导向融合蛋白。此外，我们还讨论了在过继性细胞疗法中传递抗CMV T细胞的有利特性。利用抗CMV CD8 T细胞生成CAR T细胞可促进其在体内的持久性和扩增，这是由于通过内源性（CMV-）TCR信号复合物进行了适当的共刺激。设计TCR工程化T细胞更具挑战性，因为人工TCR和内源性TCR会竞争表达。此外，还讨论了使用扩增/活化的抗CMV T细胞靶向表达CMV肽的胶质母细胞瘤。本综述突出了最重要的发现，并比较了每种策略的优缺点和挑战。最后，我们讨论了如何进一步改进抗CMV T细胞疗法以提高治疗效果。
