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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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 仍然无法治愈免疫检查点最近获得批准。针对转移性三阴性 BC (TNBC) 中的 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，但超过一半。转移性 BC 患者会发生肝脏转移，而肝脏对免疫疗法反应不佳。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，而且很少有研究项目关注 BC 肝转移。我的 K99/R00 提案将了解转移性 BC 细胞对肝脏微环境的影响。通过为我提供成为一名独立终身教授的培训来填补这一知识空白在一家研究密集型机构，开展 BC 转移（尤其是肝转移）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，以通过免疫抑制支持肺转移我的第一作者论文表明，侵袭性 TNBC。分泌细胞因子以增强促肿瘤巨噬细胞的数量目前，我正在测试其影响。血红素加氧酶-1 (HO-1) 的 TNBC 血红素代谢通过其代谢产物胆红素对免疫抑制 (BR). 我首次证明 TNBC 细胞分泌 BR 来改变巨噬细胞极化和然而，HO-1 和 BR 从未在 BC 肝转移中进行过研究，即使我的研究也如此。初步数据和其他人的工作表明，患有肝病的 BC 患者中 HO-1 和 BR 升高与转移到其他部位的转移相比，该提案的总体目标是：1) 测试肿瘤细胞-HO-1通过其抑制性调节对转移性肝脏中免疫细胞的影响细胞因子和BR；2）评估HO-1和PD-1联合抑制对肝转移的影响生长；3) 测试 BC 肝转移代谢重编程对 HO-1 表达的影响。在指导的K99阶段，我将与动物手术、肝病、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。在他们的指导下，我将通过以下方式测试 BC 肝转移-HO-1 对检查点抑制剂耐药性的影响在整个 K99 和 R00 阶段，我将促进 T 细胞介导的免疫抑制（目标 1）。还评估肿瘤细胞 BR 对肝细胞（包括称为 Kupffer 的常驻巨噬细胞）的影响在 R00 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（目标 3). 通过这个研究计划和我在 CU AMC 的支持系统，我将推进 BC 转移领域的发展。研究并为我的独立研究生涯奠定基础，我将继续评估器官特异性代谢重连对 BC 转移局部和全身免疫抑制的影响。