Impact of heme catabolism on triple negative breast cancer metastasis via immune-suppression

血红素分解代谢通过免疫抑制对三阴性乳腺癌转移的影响

• 批准号: 9910781
• 负责人: Michelle M Williams
• 金额: $ 6.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910781
• 关键词: Bilirubin; Biological Assay; Blood; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; Breast Cancer therapy; Breast cancer metastasis; Carbon Monoxide; Catabolism; Cell physiology; Cells; Chemotherapy and/or radiation; Clinical; Clinical Trials; Data; Diagnosis; Disease; Disease model; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial; Epithelium; Flow Cytometry; Genes; Heme; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunofluorescence Immunologic; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Iron; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Measures; Mesenchymal; Metastatic Neoplasm to the Lung; Metastatic breast cancer; MicroRNAs; Modeling; Mus; Neoplasm Metastasis; Paclitaxel; Pathway interactions; Patients; Pharmacology; Pre-Clinical Model; Primary Neoplasm; Production; Quantitative Reverse Transcriptase PCR; Recurrence; Refractory; Resistance; Role; Sampling; Serum; Site; T-Lymphocyte; Testing; Tumor Cell Line; Tumor stage; Tumor-Derived; Tumor-infiltrating immune cells; anti-tumor immune response; breast cancer progression; cancer immunotherapy; cancer subtypes; cell motility; cell type; chemotherapy; clinically relevant; epithelial to mesenchymal transition; experimental study; heme oxygenase-1; immune checkpoint blockade; immune function; inhibitor/antagonist; knock-down; macrophage; malignant breast neoplasm; mortality; mouse model; neoplastic cell; new therapeutic target; novel; paracrine; pre-clinical; programs; response; restoration; small hairpin RNA; standard of care; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor metabolism; tumor microenvironment; tumor progression

Abstract/Project Summary Triple negative breast cancer (TNBC) has more frequent and rapid metastasis than other breast cancer (BC) subtypes and >20% of patients progress on standard of care therapies within 5 years of diagnosis. Increased early invasiveness could be a result of epithelial to mesenchymal transition (EMT), which many TNBCs have partially undergone to increase cell motility, induce chemotherapy resistance, and promote immune evasion. Reversal of EMT using the micro-RNA miR-200c revealed several immune-suppressive catabolizing enzymes that are increased in mesenchymal-like BCs when compared to more epithelial counterparts, such as HMOX1 (heme oxygenase-1, HO-1). Interestingly, HO-1 is expressed in many cell types in the tumor microenvironment and previous studies show that targeting HO-1 in immune cells can limit tumor progression in preclinical models. However, there is a gap in knowledge regarding the role of breast tumor cell- HO-1 and its catabolites in metastasis, chemotherapy resistance, and immune evasion. My preliminary data showed that HO-1 expression was increased in lung metastases from two TNBC-like mammary tumor models when compared to their respective primary tumors. In an additional spontaneous metastasis model, HO-1 expression was also increased in lung metastases. Previous studies and my preliminary results also show that chemotherapy induces HO-1 expression. Given the important role HO-1 may have in breast tumor progression, it is critical to further investigate HO-1 in TNBC cells during metastasis and chemotherapy resistance, which I will study in Aim 1. HO-1 targeting with a clinically approved HO inhibitor will also be explored and compared to tumor cell specific HO-1 inhibition (shRNA) in clinically relevant, immune- competent TNBC-like mouse models. HO-1 degrades heme to produce catabolites that suppress normal immune cell function in a paracrine manner. One such catabolite bilirubin (BR) has powerful immune-suppressive roles in other diseases, but has not been explored in cancers as an immunosuppressant. My preliminary data further demonstrate that BR is immune-modulatory and showed that BR treatment altered the function of macrophages by limiting expression of M1 polarization genes and by halting efferocytosis, macrophage engulfment of dead cells. Previous studies show that serum BR levels increase after chemotherapy treatment in BC patients. Therefore, it is essential to understand whether elevated HO-1 expression during breast tumor progression can enhance tumor-derived bilirubin that in turn limits immune cell function. This idea will be assessed in Aim 2 where I will study the impact of bilirubin on tumor immune-suppression. Together, the aims proposed herein will determine if HO-1 is a novel clinical target to limit metastasis and reactivate the anti-tumor immune response in a non-contact dependent manner. These studies could reveal new treatment strategies with the potential to enhance the efficacy of current TNBC therapies such as chemotherapy and checkpoint blockade.

摘要/项目摘要 与其他乳腺癌相比，三重阴性乳腺癌（TNBC）具有更频繁和快速的转移 （BC）亚型和> 20％的患者在诊断后的5年内在护理疗法上的进展。 提高早期侵入性可能是间充质转变（EMT）上皮的结果，其中许多 TNBC已部分经历以增加细胞运动，诱导化学疗法抗性并促进 免疫逃避。使用微RNA miR-200C逆转EMT显示出几种免疫抑制 与更上皮相比，在间充质样BC中增加的分解代谢酶 对应物，例如HMOX1（血红素加氧酶-1，HO-1）。有趣的是，HO-1在许多细胞类型中表达 在肿瘤微环境和先前的研究中，在免疫细胞中靶向HO-1可以限制肿瘤 临床前模型中的进展。但是，关于乳腺肿瘤细胞的作用的知识存在差距 HO-1及其分解代谢物在转移，化学疗法抗性和免疫逃避中。 我的初步数据表明，在两个TNBC样的肺转移中，HO-1表达增加了 与各自的原发性肿瘤相比，乳腺肿瘤模型。额外的自发 转移模型，HO-1表达在肺转移中也增加了。以前的研究和我的 初步结果还表明化学疗法诱导HO-1表达。考虑到重要角色HO-1可能 在乳腺肿瘤的进展中，至关重要的是在转移和 化学疗法耐药性，我将在AIM 1中进行研究。 还可以探索并与临床相关的免疫 - 有能力的TNBC样小鼠模型。 HO-1降解血红素产生可抑制旁分泌中正常免疫细胞功能的分解代谢物 方式。一种这样的分解代谢物胆红素（BR）在其他疾病中具有强大的免疫抑制作用，但具有 在癌症中没有作为免疫抑制剂探索。我的初步数据进一步表明BR是 免疫调节，并表明BR治疗通过限制表达改变了巨噬细胞的功能 M1极化基因和停止吞噬作用，巨噬细胞吞噬死细胞。先前的研究 表明卑诗省患者化疗后血清BR水平升高。因此，必须 了解乳腺肿瘤进展过程中HO-1表达是否可以增强肿瘤的衍生 胆红素又限制了免疫细胞功能。这个想法将在AIM 2中进行评估，我将研究 胆红素对肿瘤免疫抑制的影响。同时，本文提出的目标将确定HO-1是否是 一个新的临床靶标，以限制转移并重新激活非接触中的抗肿瘤免疫反应 依赖方式。这些研究可以揭示新的治疗策略，以增强 当前TNBC疗法（例如化学疗法和检查点阻滞）的功效。