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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结