Replicating viral vector platform exploits alarmin signals for potent CD8(+) T cell-mediated tumour immunotherapy.
Replicating viral vector platform exploits alarmin signals for potent CD8(+) T cell-mediated tumour immunotherapy.
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DOI：
10.1038/ncomms15327
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发表时间：
2017-05-26
影响因子：
16.6
通讯作者：
Pinschewer DD
中科院分区：
文献类型：
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作者：
Kallert SM;Darbre S;Bonilla WV;Kreutzfeldt M;Page N;Müller P;Kreuzaler M;Lu M;Favre S;Kreppel F;Löhning M;Luther SA;Zippelius A;Merkler D;Pinschewer DD
病毒感染导致alarmin释放并引发有效的细胞毒性效应T淋巴细胞（CTLeff）应答。相反，诱导保护性肿瘤特异性CTLeff及其在肿瘤中的募集仍然是具有挑战性的任务。在这里，我们表明，淋巴细胞性脉络丛脑膜炎病毒（LCMV）可以被改造，作为一个复制能力，稳定减毒的免疫治疗载体（artLCMV）。artLCMV将肿瘤相关抗原递送至树突状细胞，用于有效的CTL引发。与复制缺陷型载体不同，artLCMV还靶向表达alarmin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诱导的CTLeff应答比复制缺陷型载体诱导的那些应答具有更高的幅度和功能性。artLCMV免疫疗法的上级抗肿瘤功效取决于白细胞介素-33信号传导，并且大量CTLeff流入触发肿瘤微环境的炎性转化。我们的观察表明，复制病毒递送系统可以释放alarmins以提高抗肿瘤功效。这些机制性的见解可能超过围绕癌症免疫治疗中复制病毒载体的安全性问题。病毒触发有效的细胞毒性T细胞反应，而抗肿瘤免疫一直难以建立。在这里，作者设计了一种用于肿瘤相关抗原的复制病毒递送系统，该系统诱导小鼠的alarmin释放，先天激活和保护性抗肿瘤免疫。
Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses. Conversely, the induction of protective tumour-specific CTLeff 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 CTLeff 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 CTLeff 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. Viruses trigger potent cytotoxic T cell responses, whereas anti-tumour immunity has been difficult to establish. Here the authors engineer a replicating viral delivery system for tumour-associated antigens, which induces alarmin release, innate activation and protective anti-tumour immunity in mice.