Lung epithelial lineage-specific factors in the control of immune system evasion genes in tumor cells

肺上皮谱系特异性因子控制肿瘤细胞免疫系统逃避基因

基本信息

批准号：
10201859
负责人：
Maria Isabel Ramirez
金额：
$ 7.8万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201859
关键词：
Adopted Adult Aggressive behavior Binding Binding Proteins Binding Sites Cancer Control Cancer Patient Cancer cell line Carcinoma Cells Coculture Techniques Combined Modality Therapy DNA Data Set Development Disease Distal Epithelial Epithelial Cells Equilibrium Fetal Lung Foundations Future Gene Expression Genes Goals Human Human body Immune Immune Evasion Immune checkpoint inhibitor Immune response Immune system Immunomodulators Immunotherapy In Vitro JAK2 gene Knowledge Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Mind Molecular Oncogenes Oncogenic Pathologist Pathway interactions Patients Pattern Play Population Promoter Regions Property Pulmonology Reporting Role STAT3 gene Scientist Shapes System T-Cell Activation Testing Thyroid Gland Thyroid carcinoma Transcriptional Activation Tumor Suppressor Proteins Untranslated RNA base cancer cell cancer therapy checkpoint therapy effective therapy experimental study fetal gain of function immune activation immune checkpoint lung Carcinoma lung cancer cell lung small cell carcinoma neoplastic cell novel novel therapeutics organ growth prevent programmed cell death ligand 1 promoter recruit response transcription factor tumor tumor progression tumor-immune system interactions

项目摘要

ABSTRACT Cancer cells that are capable of escaping host immune system defenses typically adopt more aggressive behaviors. Novel immunotherapies targeting these mechanisms are now successfully employed in the treatment of many cancers, including highly aggressive forms of lung cancer. However, these therapies do not limit cancer progression in all patients, emphasizing a need for more effective immune-modulating drugs. Ultimately, however, to develop these new treatments, scientists first need to understand the mechanisms by which cancer cells control the expression of immune evasion genes, also called immune checkpoints. Lineage-specific transcription factors that establish cell fate during organ development also play functions in cancer as lineage- specific tumor drivers. In the lung, the lineage-specific transcription factor NKX2-1 (TTF1), which is critical for epithelial development, shows pro- and anti-oncogenic activity in lung cancer depending on cell context. Moreover, its expression in cancer cells has been shown to shape the tumor immune microenvironment. We have recently reported that NKX2-1-AS1, an antisense long noncoding RNA overlapping the NKX2-1 promoter, is abundantly expressed in human fetal and adult lung epithelial cells, and its levels are further increased in lung cancer, matching NKX2-1 patterns. Furthermore, we found that relative levels of NKX2-1 and NKX2-1-AS1 vary considerably among different cancer cell populations and that NKX2-1 and NKX2-1-AS1 have opposing effects on the expression of the immune checkpoint gene PD-L1. In preliminary analysis, we discovered that NKX2-1 and NKX2-1AS1 also have opposing effects on the control of various other genes involved in immune system evasion. These results highlight a novel mechanism by which lung cancer cells can balance host-immune responses while controlling intrinsic cancer cell properties. Based on these findings, we hypothesize that lung cancer cells, through the lung epithelial lineage-specific factors NKX2-1 and NKX2-1-AS1, control multiple immune checkpoint genes and the escape of cancer cells from the immune system attack. We will test this hypothesis in two Aims. In Aim 1, we will define in vitro the molecular mechanism by which NKX2-1-AS1 limits the expression of genes involved in immune system evasion in lung cancer cell lines through the interaction with NKX2-1 and other key transcription factors such as STAT3. In Aim 2, we will test, using a co-culture system, the functional effect of different epithelial NKX2-1-AS1 and NKX2-1 expression ratios on the activation of T-cells. These studies have the potential to impact the field of pulmonary medicine significantly and transform the way we understand how lung epithelial-lineage factors control pulmonary immune responses, laying the foundation for new and more effective anti-cancer therapies.

抽象的能够逃避宿主免疫系统防御的癌细胞通常会采取更具攻击性的行为行为。针对这些机制的新型免疫疗法现已成功用于治疗许多癌症，包括高度侵袭性的肺癌。然而，这些疗法并不能限制癌症所有患者的病情进展，强调需要更有效的免疫调节药物。最终，然而，为了开发这些新疗法，科学家首先需要了解癌症发生的机制细胞控制免疫逃避基因的表达，也称为免疫检查点。血统特定在器官发育过程中决定细胞命运的转录因子也在癌症中发挥谱系作用特定的肿瘤驱动因素。在肺中，谱系特异性转录因子 NKX2-1 (TTF1) 对上皮发育，根据细胞环境在肺癌中显示出促癌和抗癌活性。此外，它在癌细胞中的表达已被证明可以塑造肿瘤免疫微环境。我们最近报道NKX2-1-AS1，一种与NKX2-1启动子重叠的反义长非编码RNA，在人胎儿和成人肺上皮细胞中大量表达，并且其水平在肺中进一步升高癌症，匹配 NKX2-1 模式。此外，我们发现 NKX2-1 和 NKX2-1-AS1 的相对水平有所不同 NKX2-1 和 NKX2-1-AS1 具有相反的作用，不同的癌细胞群之间存在显着差异免疫检查点基因 PD-L1 的表达。初步分析，我们发现NKX2-1 NKX2-1AS1 对参与免疫系统的各种其他基因的控制也有相反的作用逃避。这些结果凸显了肺癌细胞平衡宿主免疫的新机制反应，同时控制癌细胞的内在特性。基于这些发现，我们假设肺癌细胞，通过肺上皮谱系特异性因子NKX2-1和NKX2-1-AS1，控制多种免疫检查点基因和癌细胞逃避免疫系统攻击的研究。我们将测试这个两个目标的假设。在目标 1 中，我们将在体外定义 NKX2-1-AS1 限制的分子机制肺癌细胞系中参与免疫系统逃避的基因的表达，通过与 NKX2-1 和其他关键转录因子，例如 STAT3。在目标 2 中，我们将使用共培养系统测试不同上皮NKX2-1-AS1和NKX2-1表达比例对T细胞活化的功能影响。这些研究有可能对肺医学领域产生重大影响并改变呼吸医学的方式我们了解肺上皮谱系因子如何控制肺部免疫反应，奠定了基础寻找新的、更有效的抗癌疗法。