RIG-I activation is critical for responsiveness to checkpoint blockade
RIG-I activation is critical for responsiveness to checkpoint blockade
复制标题
DOI：
10.1126/sciimmunol.aau8943
复制
发表时间：
2019-09-01
影响因子：
24.8
通讯作者：
Poeck, Hendrik
中科院分区：
文献类型：
--
作者：
Heidegger, Simon;Wintges, Alexander;Poeck, Hendrik
实现对免疫检查点抑制剂的持久临床应答仍然是一个挑战。在这里，我们证明了抗CTLA-4及其与抗PD-1的组合的免疫疗法依赖于细胞溶质RNA受体RIG-I的肿瘤细胞内在激活。从机制上讲，肿瘤细胞内在的RIG-I信号转导诱导caspase-3介导的肿瘤细胞死亡，CD 103（+）树突状细胞交叉呈递肿瘤相关抗原，随后肿瘤抗原特异性CD 8（+）T细胞扩增，以及它们在肿瘤组织内的积累。一致地，在肿瘤和非恶性宿主细胞中用5 '-三磷酸化RNA治疗性靶向RIG-I有效地增强了CTLA-4检查点阻断在几种临床前癌症模型中的功效。在人类中，原发性黑色素瘤样本的转录组分析揭示了DDX 58（编码RIG-I的基因）、T细胞受体和抗原呈递途径活性的高表达与总生存期延长之间的强相关性。此外，在用抗CTLA-4检查点阻断治疗的黑素瘤患者中，高DDX 58 RIG-I转录活性与持久的临床应答显著相关。因此，我们的数据确定了肿瘤及其微环境中RIG-I信号传导的激活是检查点通道介导的癌症免疫治疗的关键组成部分。
Achieving durable clinical responses to immune checkpoint inhibitors remains a challenge. Here, we demonstrate that immunotherapy with anti-CTLA-4 and its combination with anti-PD-1 rely on tumor cell-intrinsic activation of the cytosolic RNA receptor RIG-I. Mechanistically, tumor cell-intrinsic RIG-I signaling induced caspase-3-mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103(+) dendritic cells, subsequent expansion of tumor antigen-specific CD8(+) T cells, and their accumulation within the tumor tissue. Consistently, therapeutic targeting of RIG-I with 5'-triphosphorylated RNA in both tumor and nonmalignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade in several preclinical cancer models. In humans, transcriptome analysis of primary melanoma samples revealed a strong association between high expression of DDX58 (the gene encoding RIG-I), T cell receptor and antigen presentation pathway activity, and prolonged overall survival. Moreover, in patients with melanoma treated with anti-CTLA-4 checkpoint blockade, high DDX58 RIG-I transcriptional activity significantly associated with durable clinical responses. Our data thus identify activation of RIG-I signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor-mediated immunotherapy of cancer.