Nrf2, immune cells and lung cancer

Nrf2、免疫细胞和肺癌

• 批准号: 10378530
• 负责人: Karen T. Liby
• 金额: $ 34.12万
• 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/10378530
• 关键词: Address; Animal Model; Anti-Inflammatory Agents; Archives; Area; Beta Carotene; Cancer Etiology; Cancer Patient; Cell secretion; Cells; Cessation of life; Chemoprevention; Chemoresistance; Chronic Disease; Chronic Kidney Failure; Clinical; Clinical Treatment; Clinical Trials; Colon Carcinoma; 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; 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; Pharmacology; 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; Testing; Time; Tobacco use; Tumor Burden; Tumor Pathology; 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; immunoregulation; in vitro activity; in vivo; inhibitor; lung cancer cell; lung cancer prevention; lung carcinogenesis; lung development; macrophage; malignant breast neoplasm; neoplastic cell; new therapeutic target; novel; 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，美国肺癌的发病率有所下降，但肺癌 癌症仍然是癌症死亡的主要原因。引入新的靶向疗法和 免疫疗法对某些基因突变的患者是有益的，但 肺癌的发病率仍然低到令人无法接受的水平。曾经吸烟的人患肺癌的风险仍然很高，而且 这些患者将受益于早期使用安全、有效的药物进行干预。激活的饮食成分 Nrf2/Keap1细胞保护通路在临床前模型中抑制肺癌和其他癌症的发展 并降低人类患癌症的风险。Nrf2的基因失活增加了从 环境挑战。然而，已经在肺和其他组织中发现了Nrf2或Keap1突变 癌症，导致该通路的结构性激活、肿瘤存活和对化疗的抵抗。 出乎意料的是，我们最近在Nrf2基因敲除(KO)的肺部和肿瘤中发现了一个新的免疫信号 小鼠与野生型(WT)小鼠进行比较。免疫细胞的变化(促进肿瘤的数量较多 巨噬细胞和髓系来源的抑制细胞(MDSCs)和降低的细胞毒性T细胞)和表达 在30多个免疫反应基因中，包括一系列与人类肺癌有关的细胞因子， 在Nrf2 KO小鼠的肺癌中被鉴定。Nrf2KO小鼠的肺癌负担也高于 WT小鼠。这些结果证实了Nrf2的保护作用，甚至在晚期癌症发生中也是如此，并提示 免疫细胞中Nrf2的激活可能有利于肺癌的预防或治疗。这些研究 是临床相关的，因为三萜类CDDO-Me(CDDO-Me)正在进行第三阶段试验 几种慢性病。这种有效的Nrf2激活剂减少了肺肿瘤的数量、大小和病理。 用于预防或治疗肺癌。CDDO-Me是一种有效的抗炎药， 抑制炎症和致癌的机制可以是Nrf2依赖的，也可以是独立的。我们 假设巨噬细胞、骨髓间充质干细胞和T细胞对Nrf2的依赖调节可以抑制肺 致癌。此外，我们假设CDDO-Me对Nrf2的药理激活将 抑制促肿瘤免疫细胞的渗透，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Nrf2激活剂和 抑制物以a)定义随着肺癌进展免疫细胞群的变化，b)测试 在体外和体内调节免疫细胞活性的NRF2的药理激活剂和抑制剂，以及c) 比较Nrf2激活剂和抑制剂防治实验性肺癌的疗效。 我们还将通过表征Nf2通路在两种免疫系统中的激活情况，将我们的结果扩展到人类NSCLC 不同分期、不同分级的人肺癌标本中的细胞和肿瘤细胞。