Understanding the impact of chemotherapy on breast cancer metastasis and immune function in the liver

了解化疗对乳腺癌转移和肝脏免疫功能的影响

基本信息

批准号：
10638917
负责人：
Sandra S McAllister
金额：
$ 51.02万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-07 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638917
关键词：
Adjuvant Chemotherapy Affect Anthracycline Bar Codes Biopsy Specimen Brain Breast Cancer Cell Breast Cancer Patient Breast Cancer therapy Breast biopsy Breast cancer metastasis CD8-Positive T-Lymphocytes Cell physiology Cells Chemotherapy-Oncologic Procedure Clinical Clone Cells Combination Drug Therapy Cyclophosphamide Cytotoxic T-Lymphocytes Data Data Set Detection Diagnosis Drug resistance FDA approved Goals Heterogeneity Immune Immune checkpoint inhibitor Immune system Immunofluorescence Immunologic Immunosuppression Impairment Investigation Knowledge Life Liver Lung Lymphocyte Malignant Neoplasms Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Methods Modeling Molecular Mus Natural Killer Cells Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Organ Patient imaging Patients Pre-Clinical Model Primary Neoplasm Prior Chemotherapy Process Prognosis Proliferating Property Radiation Resistance Sampling Site Specimen Stains T-Lymphocyte Testing Tissue Sample Tissues Treatment Protocols Tumor Immunity Tumor-infiltrating immune cells Work body system cancer cell chemotherapy clinical development cohort design effective therapy fitness high dimensionality immune function immune system function immunosuppressed improved malignant breast neoplasm mouse model multiple omics neoplastic cell new technology novel therapeutic intervention peripheral blood pre-clinical prevent receptor response standard care success taxane transcriptome sequencing treatment strategy triple-negative invasive breast carcinoma tumor tumor growth tumor heterogeneity tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Project Summary Despite treatment with neoadjuvant chemotherapy, 30-40% of patients diagnosed with early-stage triple- negative breast cancer (TNBC) develop metastasis and die of their cancer. Part of standard treatment for TNBC includes anthracycline-cyclophosphamide and taxane-based (AC-T) chemotherapy, radiation, and surgery. Combination chemotherapy with immune checkpoint inhibitors (ICI) that target T-cell inhibitory receptors are now FDA-approved for early stage and metastatic TNBC. Despite promising trial results, most patients with metastatic TNBC do not experience durable long-lasting benefits, particularly those whose tumors progressed on prior chemotherapy. Although proliferating cancer cells are the intended targets, systemic chemotherapy clearly impacts other organ systems. This includes detrimental effects on the immune system, such as elimination of cytotoxic T cells. Thus, if chemotherapy impairs anti-tumor immune cells, it would limit ICI efficacy. A major challenge to the field is that we do not understand how chemotherapy impacts immune function or tumor cell fitness in metastatic microenvironments. In our TNBC mouse models, AC-T chemotherapy reduced primary tumor growth and lung metastasis. Surprisingly, liver metastasis, which is a predominant metastatic site in TNBC patients, was significantly enhanced in the AC-T-treated mice. We also observed markers of immunosuppression in the liver after chemotherapy in both our mouse models and clinical samples. We hypothesize that the liver is specifically immunosuppressed by chemotherapy, thus making the liver more hospitable for TNBC metastasis and reducing ICI efficacy. Our objective is to understand how chemotherapy impacts the liver immune microenvironment and TNBC liver metastasis, and to identify pre-clinical strategies that prevent liver immunosuppression and metastasis. We will use our TNBC lung metastasis models and our highly sensitive molecular barcoding method for metastasis detection. We will identify tumor cell clones that grow in metastatic sites and if the clonal composition changes in response to chemotherapy treatment. We will also determine whether those clones are inherently sensitive/resistant to chemotherapy or if their response to chemotherapy relies on the metastatic microenvironment. We will perform high dimensional immune-profiling of primary tumors and liver from chemotherapy-treated tumor-free and tumor-bearing mice using single cell multi-omic approaches. We will assess immune function of cells derived from metastatic sites in the mouse models. We will validate our findings by multiplex immunofluorescence staining on patient biopsy samples taken from metastatic sites. We will identify treatment regimens that target tumor cells while protecting anti-tumor immune cells. Our proposed studies will deepen our understanding of the systemic effects of chemotherapy, not only on breast cancer cells that spread to various organs but also on immune cells in those organs. Success in our line of investigation will identify new treatment approaches that are effective against breast cancer but do not diminish critical immune cells.

项目概要尽管接受新辅助化疗治疗，仍有 30-40% 的患者被诊断为早期三重癌症阴性乳腺癌 (TNBC) 发生转移并死于癌症。 TNBC 标准治疗的一部分包括蒽环类环磷酰胺和紫杉烷类 (AC-T) 化疗、放疗和手术。现在，针对 T 细胞抑制性受体的免疫检查点抑制剂 (ICI) 联合化疗 FDA 批准用于早期和转移性 TNBC。尽管试验结果有希望，但大多数患有转移性癌症的患者 TNBC 不会带来持久的长期益处，特别是那些肿瘤在既往治疗中出现进展的患者化疗。尽管增殖的癌细胞是预期目标，但全身化疗显然影响其他器官系统。这包括对免疫系统的有害影响，例如消除细胞毒性T细胞。因此，如果化疗损害抗肿瘤免疫细胞，就会限制 ICI 的疗效。一个专业该领域面临的挑战是我们不了解化疗如何影响免疫功能或肿瘤细胞转移微环境中的适应性。在我们的 TNBC 小鼠模型中，AC-T 化疗减少了原发性肿瘤生长和肺转移。令人惊讶的是，肝转移是 TNBC 的主要转移部位在 AC-T 治疗的小鼠中，这种情况显着增强。我们还观察了免疫抑制标志物在我们的小鼠模型和临床样本中化疗后的肝脏中。我们假设肝脏是通过化疗特异性免疫抑制，从而使肝脏更适合 TNBC 转移并降低 ICI 疗效。我们的目标是了解化疗如何影响肝脏免疫微环境和 TNBC 肝转移，并确定预防肝转移的临床前策略免疫抑制和转移。我们将使用我们的 TNBC 肺转移模型和我们的高灵敏度分子条形码方法转移检测。我们将识别在转移部位生长的肿瘤细胞克隆，以及克隆组成是否对化疗治疗反应的变化。我们还将确定这些克隆是否本质上是对化疗敏感/耐药，或者他们对化疗的反应是否依赖于转移性肿瘤微环境。我们将对原发性肿瘤和肝脏进行高维免疫分析使用单细胞多组学方法对经过化疗的无瘤和荷瘤小鼠进行治疗。我们将评估小鼠模型中转移部位细胞的免疫功能。我们将验证我们的发现对取自转移部位的患者活检样本进行多重免疫荧光染色。我们将确定针对肿瘤细胞同时保护抗肿瘤免疫细胞的治疗方案。我们提出的研究将加深我们对化疗的全身影响的理解，而不仅仅是对扩散的乳腺癌细胞的影响不仅影响各种器官，还影响这些器官中的免疫细胞。我们调查的成功将发现新的对乳腺癌有效但不会减少关键免疫细胞的治疗方法。