Targeting LKB1-null lung adenocarcinoma with innate immune system

利用先天免疫系统靶向 LKB1 缺失的肺腺癌

• 批准号: 10752833
• 负责人: Wei Zhou
• 金额: $ 43.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-12 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752833
• 关键词: Adoptive Transfer; Animals; Antibodies; Antigen Presentation; Biological Assay; Cancer Model; Cancer cell line; Cell Line; Cell Therapy; Cells; Characteristics; DNA Adduction; Data; Data Set; Development; Disease; Exposure to; Female; Foundations; Frequencies; Genes; Genetically Engineered Mouse; Goals; Histocompatibility Antigens Class I; Human; Immune; Immune system; In Vitro; Incidence; Injections; Innate Immune System; KRASG12D; Lung; Lung Adenocarcinoma; MHC Class I Genes; Malignant neoplasm of lung; Mediating; Meta-Analysis; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mus; Mutate; Mutation; Natural Immunity; Natural Killer Cells; Patients; Predisposition; Regulation; Resistance; SCID Mice; STK11 gene; Sex Bias; Smoking; Somatic Mutation; Structure of parenchyma of lung; Subgroup; Tail; The Cancer Genome Atlas; Tumor Antigens; Tumor Suppressor Proteins; Veins; Work; X Inactivation; adaptive immunity; cell killing; dimensional analysis; disorder control; disorder subtype; effective therapy; immune checkpoint blockade; in vivo; innate immune mechanisms; insight; interest; lung cancer cell; lung development; male; molecular targeted therapies; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; prevent; sex; targeted treatment; trend; tumor; tumor microenvironment

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.

项目摘要 肿瘤抑制剂LKB1是肺腺癌（LUAD）中最常见的突变基因之一。这 肿瘤亚组对免疫检查点阻滞疗法具有抗性，不适合分子靶向 疗法。具有LKB1突变的LUAD通常与吸烟有关。即使女性更容易受到 肺中与吸烟相关的DNA-ADDUCT形成，LKB1突变的LUAD的频率明显降低 在多个大型研究中，女性比男性。基本机制尚不清楚，主要是因为 缺乏研究这种现象的合适模型。我们以前建立了一个遗传 FVB/N背景中的工程鼠标模型（GEMM），可以在肺中形成KRASG12D/LKB1NULL（LUAD） 在肿瘤特征和肿瘤微环境中，具有与人类LUAD相似的特征。荟萃分析 我们的GEMM模型显示，男性的LUAD形成为97％，而女性为58％。我们也建立了 来自我们GEMM的肺癌细胞系，以及通过注射尾静脉注射的肺转移 合成动物在女宿主中也遇到了强烈的性偏见。有趣的是，这种性偏见也可能是 在免疫受损的小鼠中观察到，例如缺乏适应性免疫的SCID小鼠。因此，我们 假设某些女宿主的先天免疫可以消除LKB1突变的LUAD。在这里，我们将（i） 确定为什么lkb1突变luad容易受到这种先天免疫力的影响，以及（ii）固有的群体 免疫细胞负责消除某些雌性宿主中的LKB1-LUAD。阐明这种机制 应该为开发LKB1突变luad的新治疗策略提供新的见解。