Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer.
Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer.
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DOI：
10.1158/2159-8290.cd-18-0689
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发表时间：
2019-01
期刊：
影响因子：
28.2
通讯作者：
Barbie DA
中科院分区：
文献类型：
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作者：
Kitajima S;Ivanova E;Guo S;Yoshida R;Campisi M;Sundararaman SK;Tange S;Mitsuishi Y;Thai TC;Masuda S;Piel BP;Sholl LM;Kirschmeier PT;Paweletz CP;Watanabe H;Yajima M;Barbie DA
KRAS驱动的肺癌经常失活TP53和/或STK11/LKB1，定义了与新出现的临床相关性的肿瘤亚类。具体地说，KRAS-LKB1(KL)突变肺癌侵袭性特别强，缺乏PD-L1，对免疫检查点阻断(ICB)的反应很差。尽管KRAS突变肺癌的总体突变负荷很高，但这种免疫原性受损的机制基础仍然不清楚。在这里，我们报告了LKB1的缺失导致了显著的STING表达的沉默和对细胞质双链DNA(DsDNA)的不敏感。这种作用至少部分是通过与S-腺苷甲硫氨酸水平升高相关的DNMT1和EZH2活性的过度激活而介导的，并被DNMT1上调所强化。由于与线粒体功能障碍相关的细胞质dsDNA的病理性积聚，STIN在KL细胞中的异位表达参与了TBK1下游的IRF3和STAT1信号转导，并损害了细胞的适合性。因此，沉默STING避免了LKB1失活的这些负面后果，同时促进了免疫逃逸。
KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL) mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS mutant lung cancers, remains obscure. Here we report that LKB1 loss results in marked silencing of STING expression and insensitivity to cytoplasmic double strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine (SAM) levels, and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape.