Targeting heme metabolism to initiate an immune response against breast cancer liver metastasis

项目总结/摘要 乳腺癌（BC）仍然是美国女性癌症相关死亡的第二大原因。 国家和晚期转移性BC仍然无法治愈。最近批准的免疫检查点 在转移性三阴性BC（TNBC）中靶向PD-1或PD-L1的抑制剂证明， 免疫治疗可能是降低BC死亡率的有效方法。然而，超过一半的 转移性BC患者发生向肝脏的转移，肝脏是对免疫疗法反应差的部位。 尽管患病率和死亡率很高，但很少有研究项目关注BC肝转移， 已知转移性BC细胞对肝脏微环境的影响。我的K99/R 00提案将 通过培训我成为一名独立的终身教职员工，我填补了这一知识空白 在一个研究密集型机构，有一个关于BC转移，特别是肝转移的研究项目。 我的博士后工作得到了NCI-T32和NCI-F32的支持，探索了TNBC分泌的因子， 通过免疫抑制支持肺转移。我的第一作者论文表明，积极的TNBC 分泌细胞因子以增加促肿瘤巨噬细胞的数量。目前，我正在测试 血红素加氧酶-1（HO-1）通过其代谢产物胆红素对TNBC血红素代谢的免疫抑制作用 （BR）。我第一次证明了TNBC细胞分泌BR来改变巨噬细胞极化， 功能然而，HO-1和BR从未在BC肝转移中进行过研究，尽管我的研究结果显示， 初步数据和其他人的工作表明，HO-1和BR在肝硬化患者中升高， 与转移到其他部位的患者相比。本提案的总体目标是：1） 检测肿瘤细胞HO-1通过其抑制性免疫调节对转移性肝中免疫细胞的影响。 2）评估HO-1和PD-1联合抑制对肝转移瘤的影响; 3）检测BC肝转移代谢重编程对HO-1表达的影响。 在指导K99阶段，我将与动物手术、肝病、肿瘤方面的专家合作， 免疫学和代谢组学在科罗拉多大学安舒茨医学院（CU AMC）。下 在他们的指导下，我将通过以下途径测试BC肝转移-HO-1对检查点抑制剂耐药性的影响： 促进T细胞介导的免疫抑制（目的1）。在K99和R 00阶段，我将 还评估了肿瘤细胞BR对肝细胞的影响，包括称为Kupffer的驻留巨噬细胞 细胞（目标2）。在R 00阶段，我将测试BC肝转移特异性代谢的影响， 通过HIF-1α对HO-1进行重编程，并确定这是否进一步支持局部免疫抑制（Aim 3）。有了这个研究计划和我在加州大学AMC的支持系统，我将推动BC转移领域的发展。 研究，并为我的独立研究生涯奠定基础，将继续评估 器官特异性代谢重建对BC转移中局部和全身免疫抑制的影响。

Project Summary/Abstract Breast cancer (BC) remains the second leading cause of cancer-related deaths in women in the United States and late-stage metastatic BC remains incurable. The recent approval of immune checkpoint inhibitors targeting PD-1 or PD-L1 in metastatic triple-negative BC (TNBC) demonstrates that immunotherapies may be an effective approach to decrease BC mortalities. However, over half of metastatic BC patients develop metastasis to the liver, a site that responds poorly to immunotherapies. Despite high prevalence and mortality rates, few research programs focus on BC liver metastasis and little is known about the impact of metastatic BC cells on the liver microenvironment. My K99/R00 proposal will fill this gap in knowledge by equipping me with the training to become an independent tenure-track faculty at a research-intensive institution with a program on BC metastasis, especially liver metastasis, research. My postdoctoral work supported by an NCI-T32 and NCI-F32 explored factors secreted by TNBC to support lung metastasis via immune suppression. My first-author paper showed that aggressive TNBC secrete cytokines to enhance the number of pro-tumor macrophages. Currently, I am testing the impact of TNBC heme metabolism by heme oxygenase-1 (HO-1) on immune suppression via its metabolite bilirubin (BR). I demonstrated for the first time that TNBC cells secrete BR to alter macrophage polarization and function. However, HO-1 and BR have never been studied in BC liver metastasis, even though my preliminary data and work from others showed that HO-1 and BR were elevated in BC patients with liver metastasis compared to those with metastasis to other sites. The overall goals of this proposal are to: 1) test the impact of tumor cell-HO-1 on immune cells in the metastatic liver via its regulation of suppressive cytokines and BR; 2) assess the effects of combined HO-1 and PD-1 inhibition on liver metastatic outgrowth; and 3) test the impact of BC liver metastasis metabolic reprogramming on HO-1 expression. During the mentored K99 phase, I will work with experts in animal procedures, liver disease, tumor immunology and metabolomics at the University of Colorado Anschutz Medical Campus (CU AMC). Under their guidance, I will test the effects of BC liver metastasis-HO-1 on checkpoint inhibitor resistance via promotion of T cell-mediated immune suppression (Aim 1). Throughout the K99 and R00 phases, I will also assess the impact of tumor cell-BR on liver cells including resident macrophages known as Kupffer cells (Aim 2). In the R00 phase, I will test the impact of BC liver metastasis-specific metabolic reprogramming via HIF-1α on HO-1 and determine if this further supports local immune suppression (Aim 3). With this research plan and my support system at CU AMC, I will advance the field of BC metastasis research and lay the foundation for my independent research career that will continue to assess the effects of organ-specific metabolic rewiring on local and systemic immune suppression in BC metastasis.