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.

项目总结