Nrf2, immune cells and lung cancer

Nrf2、免疫细胞和肺癌

• 批准号: 10594003
• 负责人: Karen T. Liby
• 金额: $ 19.43万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10594003
• 关键词: Acceleration; Animal Model; Anti-Inflammatory Agents; Archives; Area; Beta Carotene; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chemoprevention; Chemoresistance; Chronic Disease; Chronic Kidney Failure; Clinical; Clinical Treatment; Clinical Trials; Colon Carcinoma; Cytoprotection; Cytotoxic T-Lymphocytes; DNA Sequence Alteration; Development; Dietary Component; Early Intervention; Esters; Genetic; Human; Immune; Immune Response Genes; Immunotherapy; In Vitro; Incidence; Infiltration; Inflammation; Intervention; Investigation; Knockout Mice; Lung; Lung Adenocarcinoma; Lung Neoplasms; Macrophage; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mus; Mutation; Myeloid-derived suppressor cells; Neurofibromin 2; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Pre-Clinical Model; Predisposition; Prevention; Prevention trial; Pulmonary Pathology; Regulatory T-Lymphocyte; Resistance; Risk; Role; Safety; Sampling; Series; Signal Pathway; Smoker; Survival Rate; T-Lymphocyte; Terpenes; Testing; Time; Tobacco use; Tumor Burden; Tumor Pathology; Tumor Promotion; United States; Wild Type Mouse; cancer risk; carcinogenesis; chemotherapy; clinically relevant; comparative efficacy; cytokine; dietary supplements; environment related cancer; experimental study; former smoker; high risk; immune cell infiltrate; immunoregulation; in vitro activity; in vivo; inhibitor; lung cancer cell; lung cancer prevention; lung carcinogenesis; lung development; malignant breast neoplasm; neoplastic cell; new therapeutic target; novel; pharmacologic; phase III trial; preclinical study; prevent; pulmonary arterial hypertension; trigonelline; tumor; tumor progression; tumorigenic

Despite the reduction in incidence rates for lung cancer in the United States as tobacco use has declined, lung cancer remains the leading cause of cancer deaths. The introduction of new targeted therapies and immunotherapy has been beneficial for patients with certain genetic mutations, but the 5-year survival rates for lung cancer remain unacceptably low. Former smokers retain an elevated risk of developing lung cancer, and these patients would benefit from early intervention with a safe, effective drug. Dietary components that activate the Nrf2/Keap1 cytoprotective pathway inhibit the development of lung and other cancers in preclinical models and reduce cancer risk in humans. Genetic inactivation of Nrf2 increases susceptibility to developing cancer from environmental challenges. However, mutations in either Nrf2 or Keap1 have been identified in lung and other cancers, leading to constitutive activation of the pathway, tumor survival and resistance to chemotherapy. Unexpectedly, we recently identified a novel immune signature in the lungs and tumors of Nrf2 knockout (KO) mice compared to wildtype (WT) mice. Changes in immune cells (higher numbers of tumor-promoting macrophages and myeloid-derived suppressor cells (MDSCs) and decreased cytotoxic T cells) and expression of more than 30 immune response genes, including a series of cytokines relevant in human lung cancer, were identified in lung tumors from the Nrf2 KO mice. The Nrf2 KO mice also had a higher lung tumor burden than the WT mice. These results confirmed a protective role for Nrf2, even in late-stage carcinogenesis, and suggest that activation of Nrf2 in immune cells may be advantageous for preventing or treating lung cancer. These studies are clinically relevant, as the triterpenoid CDDO-methyl ester (CDDO-Me) is being tested in phase 3 trials for several chronic diseases. This potent Nrf2 activator reduced the number, size, and pathology of lung tumors when used for prevention or treatment of lung cancer. CDDO-Me is a potent anti-inflammatory agent, and mechanisms for suppressing inflammation and carcinogenesis can be Nrf2-dependent or independent. We hypothesize that Nrf2-dependent modulation of macrophages, MDSCs and T cells can suppress lung carcinogenesis. In addition, we hypothesize that pharmacological activation of Nrf2 with CDDO-Me will inhibit infiltration of tumor-promoting immune cells and reduce secretion of pro-tumorigenic cytokines to prevent or treat lung cancer. We will use Nrf2 WT and KO mice and pharmacological Nrf2 activators and inhibitors to a) define changes in immune cell populations as lung tumors progress, b) test the effects of pharmacological activators and inhibitors of Nrf2 to modulate immune cell activity in vitro and in vivo, and c) compare the efficacy of Nrf2 activators or inhibitors for prevention and treatment of experimental lung cancer. We will also extend our results to human NSCLC by characterizing activation of the Nf2 pathway in both immune cells and tumor cells in archived human lung cancer samples at various stages and grades.

尽管随着烟草使用的减少，美国肺癌的发病率降低了，但肺部的发病率下降了 癌症仍然是癌症死亡的主要原因。引入新的靶向疗法和 免疫疗法对某些遗传突变的患者有益，但是5年的存活率 肺癌仍然不可接受。前吸烟者保留了患肺癌的风险升高，并且 这些患者将受益于安全有效的药物的早期干预。激活的饮食成分 NRF2/KEAP1细胞保护途径抑制临床前模型中肺和其他癌症的发展 并降低人类的癌症风险。 NRF2的遗传失活增加了从 环境挑战。但是，在肺和其他中已经确定了NRF2或KEAP1中的突变 癌症导致途径的构成激活，肿瘤存活和对化疗的抗性。 出乎意料的是，我们最近在NRF2敲除（KO）的肺和肿瘤中确定了一种新型的免疫特征。 小鼠与野生型（WT）小鼠相比。免疫细胞的变化（促进肿瘤数量较高 巨噬细胞和髓样衍生的抑制细胞（MDSC）和细胞毒性T细胞降低）和表达 超过30个免疫反应基因，包括人类肺癌中有关的一系列细胞因子， 在NRF2 KO小鼠的肺肿瘤中鉴定出来。 NRF2 KO小鼠的肺部肿瘤负担还高于 WT小鼠。这些结果证实了NRF2的保护作用，即使在后期的致癌作用中也是如此，并建议 免疫细胞中NRF2的激活对于预防或治疗肺癌可能是有利的。这些研究 在临床上相关，因为三萜CDDO-甲基酯（CDDO-ME）正在3阶段试验中测试 几种慢性疾病。这种有效的NRF2激活剂减少了肺部肿瘤的数量，大小和病理 当用于预防或治疗肺癌时。 CDDO-ME是一种有效的抗炎剂， 抑制炎症和癌变的机制可以依赖于NRF2或独立。我们 假设NRF2依赖性巨噬细胞，MDSC和T细胞可以抑制肺 致癌作用。此外，我们假设使用CDDO-ME将NRF2的药理激活将 抑制促进肿瘤免疫细胞的浸润并减少促肿瘤细胞因子的分泌 预防或治疗肺癌。我们将使用NRF2 WT和KO小鼠以及药理学NRF2激活剂以及 a）抑制剂a）定义随着肺部肿瘤的进展，定义免疫细胞群体的变化，b）测试 NRF2的药理学活化剂和抑制剂在体外和体内调节免疫细胞活性，C） 比较NRF2激活剂或抑制剂预防和治疗实验性肺癌的功效。 我们还将通过表征两种免疫中NF2途径的激活来扩展到人NSCLC 在各个阶段和等级的人类肺癌样品中存档的细胞和肿瘤细胞。

项目成果

Profiling changes in metabolism and the immune microenvironment in lung tumorigenesis.

分析肺部肿瘤发生中代谢和免疫微环境的变化。

• DOI: 10.21037/atm.2019.04.33
• 发表时间: 2019
• 期刊: Annals of translational medicine
• 作者: Zhang,Di;Leal,AnaS;Rous,FawziAbu;Liby,KarenT
• 通讯作者: Liby,KarenT