The Immunomodulatory Effects of Nrf2 Activation on Macrophages in the Lung Tumor Microenvironment

项目摘要 由于目前的治疗方法无效，迫切需要开发新的肺癌治疗方法。 五年存活率保持在20%以下。肺癌微环境中的免疫浸润物 是抗癌治疗的一个很有希望的靶点。巨噬细胞构成了这个免疫群体的大部分， 以一种动态的光谱存在，既可以抗癌，也可以促癌。在发展中的肿瘤中，亲- 巨噬细胞的炎症表型有利于抗肿瘤免疫反应。为了在这个世界上生存 在炎症环境中，巨噬细胞依赖于由Nrf2途径调节的细胞保护机制。这 途径作为一种防御氧化应激的机制，保护正常、健康的细胞免受 恶变。虽然肿瘤细胞中的结构性Nrf2激活可以帮助肿瘤细胞存活，但其效果 令人惊讶的是，Nrf2的激活对肿瘤微环境中的免疫细胞的影响还没有得到充分的研究。合成的 齐墩果烷三萜类化合物是已知的NRF2途径最有效的药理激活剂， 在临床前小鼠模型中，三萜类CDDO-甲酯(CDDO-Me)具有强大的抗肿瘤活性 患上了肺癌。受肿瘤教育的骨髓源性巨噬细胞(BMDM)增加促炎作用 与抗肿瘤免疫反应和减少亲肿瘤趋化和血管生成相关的标记物 CDDO-Me治疗时的影响因素。因此，我假设通过诱导抗肿瘤巨噬细胞 在肿瘤微环境的表型中，Nrf2的激活会降低肺癌的肿瘤负担。目标1 该提案将确定巨噬细胞中Nrf2的激活是否会增强其抗肿瘤功能。AIM 2将评估 肿瘤细胞中Nrf2的激活是否极化肿瘤相关巨噬细胞以促进肿瘤生长 微环境中Nrf2的药理学激活可以克服Nrf2激活对突变的影响 肿瘤细胞减轻肿瘤负担。该提案包括一项全面的培训计划，包括授课和 在体外和体内模型系统中的实验学习，转录学，基因组编辑，和新的 活体成像技术。完成拟议的研究将为我提供必要的技能和 作为癌症生物学领域独立和协作的研究人员，需要经过严格的培训才能取得成功。

Project Summary There is a critical need for the development of new therapies for lung cancer, as current treatments are ineffective and the five-year survival rate remains below 20%. The immune infiltrate in the lung tumor microenvironment is a promising target for anti-cancer therapy. Macrophages make up the majority of this immune population and exist on a dynamic spectrum which can either be anti-cancer or cancer-promoting. In developed tumors, a pro- inflammatory phenotype in macrophages is beneficial for an anti-tumor immune response. To survive in this inflammatory environment, macrophages rely on cytoprotective mechanisms regulated by the Nrf2 pathway. This pathway serves as a defense mechanism against oxidative stress and protects normal, healthy cells from malignant transformation. While constitutive Nrf2 activation in tumor cells can aid tumor cell survival, the effect that Nrf2 activation has on immune cells in the tumor microenvironment is surprisingly underexplored. Synthetic derivatives of oleanane triterpenoids are the most potent known pharmacological activators of the Nrf2 pathway, and the triterpenoid CDDO-Methyl ester (CDDO-Me) has potent anti-tumor activity in a preclinical mouse model of lung cancer. Tumor-educated bone marrow-derived macrophages (BMDMs) increase pro-inflammatory markers associated with an anti-tumor immune response and decrease pro-tumor chemotactic and angiogenic factors when treated with CDDO-Me. Therefore, I hypothesize that by inducing an anti-tumor macrophage phenotype within the tumor microenvironment, Nrf2 activation will decrease lung tumor burden. Aim 1 of this proposal will determine if Nrf2 activation in macrophages increases their anti-tumor function. Aim 2 will evaluate whether Nrf2 activation in tumor cells polarizes tumor-associated macrophages to promote tumor growth and if pharmacological Nrf2 activation in the microenvironment can overcome the effect of Nrf2 activation in mutated tumor cells to reduce tumor burden. This proposal includes a comprehensive training plan including didactic and experimental learning in both in vitro and in vivo model systems, transcriptomics, genome editing, and novel in vivo imaging techniques. Completion of the proposed studies will provide me with the necessary skills and rigorous training needed for success as an independent and collaborative investigator in cancer biology.