Nrf2, immune cells and lung cancer

尽管随着烟草使用的减少，美国肺癌的发病率有所下降， 癌症仍然是癌症死亡的主要原因。新的靶向治疗的引入， 免疫疗法对某些基因突变的患者是有益的，但5年生存率 肺癌的发病率仍然低得令人无法接受。曾经吸烟的人患肺癌的风险更高， 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 Nrf 2/Keap 1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 降低人类患癌症的风险。Nrf 2的基因失活增加了癌症发生的易感性， 环境挑战。然而，Nrf 2或Keap 1的突变已经在肺和其他组织中被发现。 癌症，导致通路的组成性激活、肿瘤存活和对化疗的抗性。 出乎意料的是，我们最近在Nrf 2敲除（KO）的肺和肿瘤中发现了一种新的免疫特征。 野生型（WT）小鼠。免疫细胞的变化（促进肿瘤细胞数量增加） 巨噬细胞和骨髓源性抑制细胞（MDSC）和细胞毒性T细胞减少）和表达 包括一系列与肺癌相关的细胞因子在内的30多个免疫应答基因中， 在Nrf 2 KO小鼠的肺肿瘤中发现。Nrf 2 KO小鼠的肺肿瘤负荷也高于 WT小鼠。这些结果证实了Nrf 2的保护作用，即使在晚期癌症发生中也是如此，并表明 免疫细胞中Nrf 2的激活可能有利于预防或治疗肺癌。这些研究 具有临床相关性，因为三萜类化合物CDDO-甲酯（CDDO-Me）正在III期试验中进行测试， 几种慢性病。这种有效的Nrf 2激活剂减少了肺肿瘤的数量、大小和病理学 用于预防或治疗肺癌。CDDO-Me是一种有效的抗炎剂， 抑制炎症和癌发生的机制可以是Nrf 2依赖性的或独立的。我们 假设巨噬细胞、MDSC和T细胞Nrf 2依赖性调节可以抑制肺 致癌作用此外，我们假设用CDDO-Me药理学激活Nrf 2将导致 抑制促肿瘤免疫细胞浸润并减少促肿瘤细胞因子分泌 预防或治疗肺癌。我们将使用Nrf 2 WT和KO小鼠和药理学Nrf 2激活剂， 抑制剂，以a）确定随着肺肿瘤进展免疫细胞群体的变化，B）测试 在体外和体内调节免疫细胞活性的Nrf 2的药理学激活剂和抑制剂，和c） 比较Nrf 2激活剂或抑制剂预防和治疗实验性肺癌的疗效。 我们还将通过表征Nf 2通路在免疫和非免疫细胞中的激活，将我们的结果扩展到人类NSCLC。 细胞和肿瘤细胞的不同阶段和等级。

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.