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: 10370170
• 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/10370170
• 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; 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 Data; Clinical Research; 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; 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; Time; Training; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Woman; Work; anti-tumor immune response; base; 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; pathogenic microbe; pre-clinical; prognostic tool; programs; response; side effect; single cell sequencing; single-cell RNA sequencing; standard care; success; symposium; technique development; 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.

项目概要/摘要 乳腺癌是女性癌症相关死亡的主要原因。三阴性乳腺癌（TNBC） 所有主要乳腺癌亚型中预后最差。免疫疗法的预期成功并未实现 曾在TNBC 看到过。 T 细胞在 TNBC 和免疫治疗中的作用已得到充分研究，但肿瘤细胞的作用 浸润性 B 细胞 (TIL-B) 不太为人所知。 TIL-B 存在于高达 60% 的乳腺癌中，与 改善预后和对化疗的反应。有证据表明 TIL-B 直接对肿瘤产生反应 TNBC 中的抗原。利用 TNBC 中肿瘤浸润淋巴细胞的单细胞测序，我们发现 配对重链和轻链 B 细胞受体片段的低多样性高表达，这是确定的 克隆选择的证据，表明 B 细胞已经经历了亲和力成熟并且可以识别抗原。 为了克隆抗体并鉴定其在 TNBC 中的靶标，我们成功对 B 细胞进行了测序 迄今为止我们已发现的最丰富的 B 细胞克隆的受体。临床前数据还表明 B 细胞抗体产生在免疫治疗效果中发挥重要作用。根据这些数据，我们假设 TNBC 中的 B 细胞识别肿瘤相关抗原并产生生物学相关的肿瘤特异性抗原 抗体。为了检验我们的假设，我们提出以下目标：1）发现克隆选择的 B-的作用 人 TNBC 中的细胞/浆母细胞，2) 表征针对 TNBC 的内源抗体反应，以及 3) 评估免疫检查点抑制对人类 TNBC 中 B 细胞受体多样性和表型的影响。 这些目标的成功执行将支持 B 细胞在抗肿瘤免疫反应中的作用，并奠定 为开发基于 TNBC 的新型 B 细胞疗法和/或生物标志物奠定了基础。除了不断进步 科学知识，该提案为医师科学家提供培训。 Downs-Canner 博士是一名执业医师 具有细胞免疫学背景的乳腺外科肿瘤学家。她的长期目标是将她的临床 和研究专业知识来开发一个独立资助的研究项目，重点关注免疫治疗 乳腺癌。她受益于两位拥有培训临床医生科学家记录的知名导师 以及极其支持的研究和实践环境。为了实现她的长远目标， 候选人的提案包括结构化的职业发展计划和以下方面的培训：1) 生物信息学 2) 抗体 克隆技术和专业知识的发展：1) B 细胞生物学和 2) 日益复杂的假设 驱动实验设计、执行和分析。拟议的计划包括指导式体验式学习、 课程作业和会议参与、频繁的导师会议以及研究的逐步增加 独立。奖励期结束后，候选人将准备申请独立 资助她的研究计划。