RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade
RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade
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DOI：
10.1038/s41375-019-0639-x
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发表时间：
2019-11
期刊：
影响因子：
11.4
通讯作者：
M. Ruzicka;Lars M. Koenig;S. Formisano;D. F. Boehmer;B. Vick;Eva-M. Heuer;Hanna Meinl;Lorenz Kocheis
中科院分区：
文献类型：
--
作者：
M. Ruzicka;Lars M. Koenig;S. Formisano;D. F. Boehmer;B. Vick;Eva-M. Heuer;Hanna Meinl;Lorenz Kocheis
视黄酸诱导基因i （RIG-I）是一种细胞质免疫受体感应病毒RNA。它触发I型干扰素（IFN）和促炎细胞因子的释放，诱导适应性细胞免疫反应。我们研究了用短5 ' -三磷酸修饰RNA （ppp-RNA）激活全身rig - 1治疗同基因小鼠C1498急性髓性白血病（AML）的治疗潜力。在相当大比例的动物中，ppp-RNA治疗显著降低了肿瘤负担，延迟了疾病发作，并导致包括免疫记忆形成在内的完全缓解。治疗诱导的肿瘤排斥反应依赖于CD4+和CD8+T细胞，而不依赖于NK或B细胞，并依赖于宿主体内完整的IFN和线粒体抗病毒信号蛋白（MAVS）信号。有趣的是，ppp-RNA处理诱导AML细胞上的程序性死亡配体1 （PD-L1）表达，并在体内建立了对抗pd -1检查点阻断的治疗敏感性。在免疫重建的人源化小鼠中，ppp-RNA处理减少了血液和骨髓中患者来源的异种移植（PDX） AML细胞的数量，同时增加了各自组织中的CD3+T细胞计数。由于其能够建立完全缓解和免疫记忆状态，我们的研究结果表明，ppp-RNA治疗是一种很有前途的AML免疫治疗策略。
Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic immune receptor sensing viral RNA. It triggers the release of type I interferons (IFN) and proinflammatory cytokines inducing an adaptive cellular immune response. We investigated the therapeutic potential of systemic RIG-I activation by short 5′-triphosphate-modified RNA (ppp-RNA) for the treatment of acute myeloid leukemia (AML) in the syngeneic murine C1498 AML tumor model. ppp-RNA treatment significantly reduced tumor burden, delayed disease onset and led to complete remission including immunological memory formation in a substantial proportion of animals. Therapy-induced tumor rejection was dependent on CD4+and CD8+T cells, but not on NK or B cells, and relied on intact IFN and mitochondrial antiviral signaling protein (MAVS) signaling in the host. Interestingly, ppp-RNA treatment induced programmed death ligand 1 (PD-L1) expression on AML cells and established therapeutic sensitivity to anti-PD-1 checkpoint blockade in vivo. In immune-reconstituted humanized mice, ppp-RNA treatment reduced the number of patient-derived xenografted (PDX) AML cells in blood and bone marrow while concomitantly enhancing CD3+T cell counts in the respective tissues. Due to its ability to establish a state of full remission and immunological memory, our findings show that ppp-RNA treatment is a promising strategy for the immunotherapy of AML.