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

• 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
• 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

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 能够逃脱宿主免疫系统防御的癌细胞通常采用更具侵略性 行为。现在，针对这些机制的新型免疫疗法已成功地用于治疗 在许多癌症中，包括高度侵略性的肺癌。但是，这些疗法不限制癌症 所有患者的进展，强调需要更有效的免疫调节药物。最终， 但是，要开发这些新疗法，科学家首先需要了解癌症的机制 细胞控制免疫逃避基因的表达，也称为免疫检查点。特定于血统的 在器官发育过程中建立细胞命运的转录因子在癌症中也发挥作用 特定的肿瘤驱动器。在肺中，谱系特异性转录因子NKX2-1（TTF1），这对于 上皮发育，取决于细胞环境，在肺癌中表现出促肺癌和抗抗癌活性。 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 最近报道说，NKX2-1-AS1是反义长的非编码RNA，重叠了NKX2-1启动子， 在人类胎儿和成年肺上皮细胞中大量表达，肺的水平进一步升高 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 在不同的癌细胞群体中，NKX2-1和NKX2-1-AS1有相反的影响 关于免疫检查点基因PD-L1的表达。在初步分析中，我们发现NKX2-1 和NKX2-1AS1对免疫系统中其他各种基因的控制也有相反的影响 逃避。这些结果突出了一种新型机制，肺癌细胞可以平衡宿主免疫 在控制固有的癌细胞特性的同时反应。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控制多个 免疫检查点基因和癌细胞从免疫系统攻击中逃脱。我们将测试这个 两个目标的假设。在AIM 1中，我们将在体外定义NKX2-1-AS1限制的分子机制 通过与 NKX2-1和其他关键转录因子（例如STAT3）。在AIM 2中，我们将使用共培养系统测试 不同上皮NKX2-1-AS1和NKX2-1表达比对T细胞激活的功能作用。 这些研究有可能影响肺医学领域并改变方式 我们了解肺上皮线因素如何控制肺免疫反应，奠定基础 用于新的，更有效的抗癌疗法。