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，因此迫切需要开发新的肺癌治疗方法 五年生存率低于20%。肺肿瘤微环境中的免疫浸润是 一个很有前途的抗癌治疗靶点。巨噬细胞占免疫群体的大多数， 存在于动态谱上，其可以是抗癌的或促癌的。在发展中的肿瘤中， 巨噬细胞中的炎性表型有益于抗肿瘤免疫应答。为了生存 在炎症环境中，巨噬细胞依赖于由Nrf 2途径调节的细胞保护机制。这 作为一种防御机制，对氧化应激和保护正常，健康的细胞， 恶性转化虽然肿瘤细胞中的组成性Nrf 2激活可以帮助肿瘤细胞存活，但这种作用 Nrf 2激活对肿瘤微环境中免疫细胞的影响令人惊讶地未得到充分研究。合成 齐墩果烷三萜类化合物的衍生物是已知的Nrf 2途径的最有效的药理学激活剂， 并且三萜类化合物CDDO-甲酯（CDDO-Me）在临床前小鼠模型中具有有效的抗肿瘤活性 肺癌的症状受肿瘤训练的骨髓源性巨噬细胞（BMDM）增加促炎性细胞因子 与抗肿瘤免疫应答相关的标志物，并降低促肿瘤趋化性和血管生成 因此，我假设通过诱导抗肿瘤巨噬细胞， 在肿瘤微环境内的表型中，Nrf 2活化将降低肺肿瘤负荷。目标1 该提案将确定巨噬细胞中的Nrf 2活化是否增加其抗肿瘤功能。目标2将评估 肿瘤细胞中的Nrf 2活化是否极化肿瘤相关巨噬细胞以促进肿瘤生长，以及 微环境中的药理学Nrf 2激活可以克服突变的Nrf 2激活的作用。 肿瘤细胞，以减少肿瘤负荷。该提案包括一个全面的培训计划，包括教学和 实验学习在体外和体内模型系统，转录组学，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， 严格的培训需要成功作为一个独立的和合作的研究人员在癌症生物学。

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.