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

• 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
• 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

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，但30-40%的早期三重癌患者仍被诊断为癌症。 阴性乳腺癌（TNBC）发生转移并死于其癌症。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，靶向T细胞抑制性受体的免疫检查点抑制剂（ICI）的联合化疗已成为一种新的治疗方法。 FDA批准用于早期和转移性TNBC。尽管试验结果很有希望，但大多数转移性乳腺癌患者 TNBC没有经历持久的长期益处，特别是那些肿瘤在先前的治疗中进展的患者。 化疗虽然增殖的癌细胞是预期的目标，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，则会限制ICI功效。一个主要 该领域的挑战是我们不了解化疗如何影响免疫功能或肿瘤细胞， 在转移性微环境中的适应性。在我们的TNBC小鼠模型中，AC-T化疗减少了原发性肝癌。 肿瘤生长和肺转移。令人惊讶的是，作为TNBC中的主要转移部位的肝转移， 在AC-T治疗的小鼠中，患者的免疫应答显著增强。我们还观察到免疫抑制的标志物 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 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， 转移检测我们将鉴定在转移部位生长的肿瘤细胞克隆， 对化疗反应的变化。我们还将确定这些克隆体是否 对化疗敏感/耐药，或者如果他们对化疗的反应依赖于转移性肿瘤， 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化疗治疗的无肿瘤和荷瘤小鼠进行了研究。我们将 评估小鼠模型中源自转移部位的细胞的免疫功能。我们会验证我们的发现 通过对取自转移部位的患者活检样品进行多重免疫荧光染色。我们将确定 靶向肿瘤细胞同时保护抗肿瘤免疫细胞的治疗方案。我们建议的研究将 加深我们对化疗的全身效应的理解，不仅是对扩散的乳腺癌细胞， 也会影响这些器官中的免疫细胞如果我们的调查取得成功， 治疗方法对乳腺癌有效，但不会减少关键的免疫细胞。