Targeting LKB1-null lung adenocarcinoma with innate immune system

项目摘要 抑癌基因LKB1是肺腺癌中最常见的突变基因之一。这 肿瘤亚群对免疫检查点阻断治疗具有抵抗力，对分子靶向治疗不敏感 治疗。带有LKB1突变的LUAD通常与吸烟有关。即使女性更容易患上 与吸烟相关的DNA加合物在肺中的形成，LKB1突变LUAD的频率在 在多项大规模研究中，女性多于男性。潜在的机制尚不清楚，主要是因为 缺乏适当的模型来研究这一现象。我们之前在基因上建立了一种 FVB/N背景下的工程化小鼠模型(GEMM)，可在肺内形成KrasG12D/LKB1空(LUAD) 具有与人类LUAD相似的肿瘤特征和肿瘤微环境。的元分析 我们的GEMM模型显示，男性LUAD的形成比例为97%，女性为58%。我们还建立了 我们GEMM肺癌细胞株的建立和尾静脉注射建立肺转移的研究 同基因动物在雌性宿主中也遇到了强烈的性别偏见。有趣的是，这种性别偏见也可能是 在免疫受损的小鼠中观察到，如适应性免疫缺陷的SCID小鼠。因此，我们 假设某些女性宿主的先天免疫可以消除LKB1突变的LUAD。在这里，我们将(一) 确定为什么LKB1突变体LUAD对这种先天免疫易感，以及(Ii)先天免疫的哪个亚群 免疫细胞负责消除某些雌性宿主中的LKB1-LUAD。对这一机制的阐明 应该为开发LKB1突变LUAD的新治疗策略提供新的见解。

Project Summary The tumor suppressor LKB1 is one of the most frequently mutated genes in lung adenocarcinoma (LUAD). This tumor subgroup is resistant to immune checkpoint blockade therapy and is not amenable to molecularly targeted therapies. LUAD with LKB1 mutations is usually smoking-related. Even though females are more susceptible to smoking-related DNA-adduct formation in the lung, the frequency of LKB1-mutant LUAD is significantly lower in females than males in multiple large-scale studies. The underlying mechanism is not known primarily because of the lack of an appropriate model to study this phenomenon. We previously established a genetically engineered mouse model (GEMM) in FVB/N background, which can form KrasG12D/LKB1null (LUAD) in the lung with similar features to human LUAD in tumor characteristics and tumor microenvironment. A meta-analysis of our GEMM model revealed the LUAD formation at 97% in males versus 58% in females. We also established lung cancer cell lines from our GEMM, and the establishment of lung metastases through tail-vein injection in syngeneic animals also encountered a strong sex bias in female hosts. Interestingly, this sex bias can also be observed in immune-compromised mice, such as SCID mice deficient in adaptive immunity. Therefore, we hypothesize that innate immunity in some female hosts can eliminate LKB1-mutant LUAD. Here, we will (i) determine why LKB1-mutant LUAD is susceptible to this innate immunity and (ii) which subpopulation of innate immune cells is responsible for eliminating LKB1-LUAD in some female hosts. The elucidation of this mechanism should provide novel insights into developing new therapeutic strategies for LKB1-mutant LUAD.