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.

项目摘要尽管接受了新辅助化疗治疗，但有30-40％的患者被诊断阴性乳腺癌（TNBC）发展转移并死于其癌症。 TNBC标准治疗的一部分包括蒽环环磷酰胺和基于紫杉烷的（AC-T）化学疗法，放射线和手术。与免疫检查点抑制剂（ICI）组合化疗（靶标T细胞抑制受体）现在 FDA批准为早期和转移性TNBC。尽管有希望的试验结果，但大多数转移性患者 TNBC没有持久的长期益处，尤其是那些肿瘤在先前发展的好处化学疗法。尽管增殖的癌细胞是预期的靶标，但全身化疗清楚影响其他器官系统。这包括对免疫系统的不利影响，例如消除细胞毒性T细胞。因此，如果化疗会损害抗肿瘤免疫细胞，则将限制ICI功效。专业对该领域的挑战是，我们不了解化学疗法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化学疗法降低了原发性肿瘤生长和肺转移。令人惊讶的是，肝转移，这是TNBC中主要转移部位患者在AC-T处理的小鼠中显着增强。我们还观察到免疫抑制的标记在我们的小鼠模型和临床样品中化学疗法后的肝脏中。我们假设肝脏是特别是通过化学疗法进行免疫抑制的，从而使肝脏对TNBC转移更热情好客并降低ICI功效。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，并确定预防肝脏的临床前策略免疫抑制和转移。我们将使用TNBC肺转移模型和高度敏感的分子条形码方法转移检测。我们将确定在转移性位点生长的肿瘤细胞克隆，以及克隆组成响应化学疗法治疗的变化。我们还将确定这些克隆是否本质上是对化学疗法的敏感/抗性或对化疗的反应依赖于转移性微环境。我们将对原发性肿瘤和肝脏进行高维的免疫促进采用单细胞多词方法的无疗法治疗的无肿瘤和耐肿瘤的小鼠。我们将评估小鼠模型中转移位点衍生的细胞的免疫功能。我们将验证我们的发现通过从转移部位采集的患者活检样本上的多重免疫荧光染色。我们将确定靶向肿瘤细胞的治疗方案，同时保护抗肿瘤免疫细胞。我们提出的研究将加深我们对化学疗法系统作用的理解，不仅对传播的乳腺癌细胞到各种器官，但也是这些器官中的免疫细胞。在我们的调查领域的成功将确定新的对乳腺癌有效但不会减少临界免疫细胞的治疗方法。