The role of B-cells in the anti-tumor immune response in triple negative breast cancer

B 细胞在三阴性乳腺癌抗肿瘤免疫反应中的作用

• 批准号: 10619548
• 负责人: Stephanie M Downs-Canner
• 金额: $ 26.42万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-09 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619548
• 关键词: Active Learning; Affinity; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antigen Presentation; Antigen Targeting; Antigens; Antitumor Response; Award; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; Bioinformatics; Biological Markers; Biology; Breast Cancer Model; Breast Cancer cell line; Cancer Etiology; Caring; Cause of Death; Cell Therapy; Cell physiology; Cells; Cellular Immunology; Cellular biology; Cessation of life; Clinical; Clonal Expansion; Clone Cells; Cloning; Complex; Data; Data Set; Development; Development Plans; Environment; Epitopes; Experimental Designs; Face; Foundations; Funding; Generations; Goals; Human; Immune; Immune system; Immunoglobulin Somatic Hypermutation; Immunotherapy; Infiltration; Invaded; Knowledge; Light; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mentors; Monoclonal Antibodies; Mus; Patients; Persons; Phenotype; Physicians; Plasmablast; Play; Principal Investigator; Production; Prognosis; Proliferating; Protein Fragment; Reaction; Records; Research; Role; Sampling; Scientific Advances and Accomplishments; Scientist; Structure; Structure of germinal center of lymph node; Surgeon; Surgical Oncologist; T cell response; T-Lymphocyte; Techniques; Testing; The Cancer Genome Atlas; Therapeutic; Training; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Woman; Work; anti-tumor immune response; breast surgery; cancer therapy; cancer type; career development; checkpoint inhibition; checkpoint therapy; chemotherapy; cytokine; diagnostic strategy; genetic signature; improved; improved outcome; insight; malignant breast neoplasm; meetings; neoantigens; neoplasm immunotherapy; novel; overexpression; pathogenic microbe; pre-clinical; prognostic tool; programs; response; side effect; single cell sequencing; single-cell RNA sequencing; standard care; success; symposium; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Breast cancer is the leading cause of cancer-related death in women. Triple negative breast cancer (TNBC) has the poorest prognosis of all major subtypes of breast cancer. The anticipated success of immunotherapy has not been seen in TNBC. The role of T-cells in TNBC and immunotherapy has been well-studied but the role of tumor- infiltrating B-cells (TIL-B) is less well-known. Present in up to 60% of breast cancers, TIL-B are associated with improved prognosis and response to chemotherapy. Evidence suggests that TIL-B respond directly to tumor antigens in TNBC. Utilizing single-cell sequencing of tumor-infiltrating lymphocytes in TNBC, we have identified high expression of a low diversity of paired heavy and light chain B-cell receptor segments which is definitive evidence of clonal selection, suggesting B-cells have undergone affinity maturation and can recognize antigens. In order to clone antibodies and identify their targets in TNBC, we have successfully sequenced the B-cell receptors of the most abundant B-cell clones we have identified thus far. Pre-clinical data also suggests an important role for B-cell antibody production in immunotherapy efficacy. Based on these data, we hypothesize that B-cells in TNBC recognize tumor-associated antigens and produce biologically relevant tumor-specific antibodies. To test our hypothesis, we propose the following aims: 1) Discover the role of clonally selected B- cells/plasmablasts in human TNBC, 2) Characterize the endogenous antibody response against TNBC, and 3) Evaluate the impact of immune checkpoint inhibition on B-cell receptor diversity and phenotype in human TNBC. Successful execution of these aims will support a role for B-cells in the anti-tumor immune response and lay the foundation for development of novel B-cell based therapies and/or biomarkers in TNBC. In addition to advancing scientific knowledge, this proposal provides training to a physician-scientist. Dr. Downs-Canner is a practicing breast-surgical oncologist with a background in cellular immunology. Her long-term goal is to combine her clinical and research expertise to develop an independently-funded research program focused on immunotherapy in breast cancer. She benefits from two well-established mentors with track records of training clinician-scientists and an extremely supportive research and practice environment. In order to achieve her long-term goals, the candidate's proposal includes a structured career development plan and training in: 1) bioinformatics 2) antibody cloning techniques and development of expertise in: 1) B-cell biology and 2) increasingly complex hypothesis driven experimental design, execution, and analysis. The proposed plan includes mentored experiential learning, course work and conference participation, frequent mentor meetings and a gradual increase in research independence. At the completion of the award period, the candidate will be prepared to apply for independent funding for her research program.

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