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

靶向血红素代谢启动针对乳腺癌肝转移的免疫反应

• 批准号: 10523842
• 负责人: Michelle M Williams
• 金额: $ 11.43万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523842
• 关键词: Address; Animals; Antigen Presentation; Bilirubin; Biological Assay; Biology; Blocking Antibodies; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; Cancer Etiology; Cell physiology; Cells; Cessation of life; Clinical; Colorado; Conditioned Culture Media; Data; Disease; Enzymes; Faculty; Foundations; Funding; Genetic; Genetic Transcription; Glucose; Glycolysis; Goals; Heme; Hepatocyte; High Prevalence; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunosuppression; Immunotherapy; Institution; Knowledge; Kupffer Cells; Liver; Liver diseases; Mediating; Medical; Mentors; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Modeling; Mus; Neoplasm Metastasis; Organ; PD-1/PD-L1; Paper; Pathway interactions; Patients; Pharmacology; Phase; Procedures; Production; Quality of life; Regulation; Regulatory T-Lymphocyte; Research; Resistance; Shapes; Site; Specimen; Support System; Supporting Cell; T-Lymphocyte; Testing; Time; Tissues; Training; Tumor Immunity; United States; Universities; Up-Regulation; Woman; Work; aggressive breast cancer; anti-tumor immune response; career; cytokine; cytotoxic; exhaust; heme oxygenase-1; hypoxia inducible factor 1; improved; in vivo; knowledge base; liver function; macrophage; malignant breast neoplasm; metabolomics; mortality; neoplastic cell; novel; novel strategies; novel therapeutic intervention; overexpression; programmed cell death ligand 1; programmed cell death protein 1; programs; response; skills; small hairpin RNA; success; tenure track; triple-negative invasive breast carcinoma; tumor; tumor immunology; tumor metabolism

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.

项目摘要/摘要 乳腺癌仍然是美国女性癌症相关死亡的第二大原因。 状态和晚期转移性BC仍然无法治愈。最近批准的免疫检查点 转移性三阴性BC(TNBC)中针对PD-1或PD-L1的抑制剂表明 免疫疗法可能是降低BC死亡率的有效方法。然而，超过一半的人 转移性结直肠癌患者发生肝脏转移，这是一个对免疫治疗反应较差的部位。 尽管发病率和死亡率很高，但很少有研究项目关注不列颠哥伦比亚省的肝转移，也很少 已知转移性BC细胞对肝脏微环境的影响。我的K99/R00提案将 通过为我提供培训来填补这一知识空白，使我成为一名独立的终身教员 在一个研究密集的机构，有一个关于BC转移，特别是肝转移的项目，研究。 我的博士后工作得到了NCI-T32和NCI-F32的支持，探索了TNBC分泌的因素 通过免疫抑制支持肺转移。我的第一作者论文表明，攻击性的TNBC 分泌细胞因子以增加亲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)。我首次证明了TNBC细胞分泌BR来改变巨噬细胞的极化和 功能。然而，HO-1和BR在BC肝转移中从未被研究过，尽管我的 初步数据和其他人的工作表明，在有肝脏的BC患者中，HO-1和BR升高 与转移到其他部位的患者相比，有转移的患者。这项提案的总体目标是：1) 检测肿瘤细胞HO-1对肝转移瘤免疫细胞的抑制作用 细胞因子和BR；2)评估联合抑制HO-1和PD-1对肝转移的影响 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、肝脏疾病、肿瘤方面的专家一起工作 科罗拉多大学安舒茨医学院(CU AMC)的免疫学和代谢组学。在……下面 他们的指导下，我将测试BC肝转移-HO-1对检查点抑制物耐药性的影响，通过 促进T细胞介导的免疫抑制(目标1)。在整个K99和R00阶段，我将 还要评估肿瘤细胞-BR对肝细胞的影响，包括被称为Kupffer的常驻巨噬细胞 细胞(目标2)。在R00阶段，我将测试BC肝转移特异性代谢的影响 通过HIF-1α在HO-1上重新编程，并确定这是否进一步支持局部免疫抑制(AIM 3)。有了这项研究计划和我在CU 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，这将继续评估 器官特异性代谢重排对BC转移局部和全身免疫抑制的影响。