Division of Experimental Virology, Department of Biomedicine, University of Basel, Petersplatz 10, 4009 Basel, Switzerland.
Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland.
Nat Commun. 2017 May 26;8:15327. doi: 10.1038/ncomms15327.
Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTL) responses. Conversely, the induction of protective tumour-specific CTL and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTL responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTL influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy.
病毒感染会导致警报素释放，并引发强烈的细胞毒性效应 T 淋巴细胞（CTL）应答。相反，诱导保护性的肿瘤特异性 CTL 并将其募集到肿瘤中仍然是具有挑战性的任务。在这里，我们展示了淋巴细胞性脉络丛脑膜炎病毒（LCMV）可以被工程化为具有复制能力的稳定减毒免疫治疗载体（artLCMV）。artLCMV 将肿瘤相关抗原递呈给树突状细胞，以有效地诱导 CTL 应答。与复制缺陷型载体不同，artLCMV 还靶向表达警报素白细胞介素-33 的淋巴组织基质细胞。通过触发白细胞介素-33 信号，artLCMV 引发的 CTL 应答比复制缺陷型载体诱导的 CTL 应答具有更高的幅度和功能。artLCMV 免疫治疗的优越抗肿瘤疗效取决于白细胞介素-33 信号，大量 CTL 涌入会引发肿瘤微环境的炎症转化。我们的观察结果表明，复制病毒递送系统可以释放警报素来提高抗肿瘤疗效。这些机制上的见解可能超过了癌症免疫治疗中复制病毒载体的安全性担忧。
