Targeting myeloid cells to increase efficacy of immunotherapy against brain tumors.

靶向骨髓细胞以提高针对脑肿瘤的免疫疗法的功效。

• 批准号: 10571040
• 负责人: Tyler Eugene Miller
• 金额: $ 21.15万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571040
• 关键词: Academia; Address; Advisory Committees; Biological Models; Biology; Biotechnology; Brain; Brain Neoplasms; Bromodomain; CAR T cell therapy; Cancer Patient; Cells; Clinical; Communication; Cues; Cytotoxic T-Lymphocytes; Data; Development Plans; EP300 gene; Effectiveness; Effector Cell; Epigenetic Process; Faculty; Gene Silencing; General Hospitals; Genomics; Glioblastoma; Grant; Immune; Immune checkpoint inhibitor; Immune system; Immunology; Immunology procedure; Immunosuppression; Immunotherapy; Invaded; Laboratories; Leadership; Life; Macrophage; Malignant Neoplasms; Malignant neoplasm of brain; Massachusetts; Mentors; Mentorship; Methods; Microglia; Mitochondria; Modeling; Mutation Detection; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Organoids; Pathology; Patients; Peripheral; Phenotype; Physicians; Positioning Attribute; Primary Neoplasm; Professional Competence; Program Development; Recording of previous events; Recurrence; Refractory; Research; Research Proposals; Running; Sampling; Scientist; Structure; System; T cell infiltration; Technical Expertise; Techniques; Therapeutic; Training; Work; Writing; cDNA Library; cancer type; career development; cell transformation; design; experience; experimental study; genomic data; inhibitor; migration; monocyte; mutant; neoplastic cell; peripheral blood; prevent; programs; rational design; single-cell RNA sequencing; skills; small molecule; small molecule inhibitor; targeted treatment; therapeutic target; therapy design; tool; transcription factor; transcriptome; tumor; tumor microenvironment

PROJECT SUMMARY The proposed research career development program seeks to investigate the mechanism by which myeloid cells in brain tumors become immunosuppressive, preventing the immune system from controlling the tumor even in the presence of immunotherapy designed to activate it. The candidate is currently a Research Fellow in the Department of Pathology of the Massachusetts General Hospital. The proposal incorporates specific technical skills that will be required for the project including training in immune biology and advanced immune assay techniques. The structured career development plan includes training and mentorship in laboratory management, scientific leadership, research communications, grant writing, and other critical career skills. These technical and career skills will be acquired under the guidance of Dr. Bradley Bernstein, who will serve as primary mentor and has a history of trainees that obtain group leader positions in academia, as well as a Research Advisory Committee of word-class scientists including Drs. Mario Suva, John Iafrate, and Nir Hacohen. Through this comprehensive program, the candidate will acquire a unique set of clinical and research skills that will enable him to transition to an independent physician scientist faculty position with a lab focused on basic mechanisms and therapeutic opportunities in brain cancer epigenetics and immunology. The research strategy will investigate immunosuppressive tumor-associated myeloid cells in brain tumors – where they come from, the epigenetic mechanism by which they become immunosuppressive, and how to potentially transform them. Transforming or selectively killing myeloid cells that express immunosuppressive programs offers great opportunity to sensitize brain tumors to immunotherapy. However, it remains unknown if these myeloid cells come from circulating monocytes or endogenous microglia, or what make them immunosuppressive, significantly hindering the design of rational clinical strategies to target these cells in brain tumors. The aims of this proposal are to: (1) Determine the origin of immunosuppressive myeloid cell states in brain tumors, (2) identify the epigenetic regulatory factors that maintain the immunosuppressive cell program, (3) discover perturbations that eliminate or transform immunosuppressive myeloid cells. Overall, these studies will provide valuable data needed to develop targeted therapies against immunosuppressive myeloid cells and increase the efficacy of immunotherapy for brain cancer patients.

项目摘要 拟议的研究职业发展计划旨在调查该机制 脑肿瘤中的髓样细胞变得免疫抑制，以防止免疫抑制系统 即使在旨在激活它的免疫疗法的情况下控制肿瘤也可以通过。 候选人目前是马萨诸塞州病理学系的研究员 综合医院。该提案结合了特定的技术技能 项目包括免疫生物学和先进免疫测定技术的培训。这 结构化的职业发展计划包括实验室的培训和心态， 科学领导，研究沟通，赠款写作和其他关键职业技能。 这些技术和职业技能将在布拉德利·伯恩斯坦博士的指导下获得 谁将担任主要导师，并拥有培训的历史 在学术界以及包括Drs在内的文字科学家的研究咨询委员会。 Mario Suva，John Iafrate和Nir Hacohen。通过这个综合计划，候选人 将获得一套独特的临床和研究技能，使他能够过渡到 独立的物理科学家教师职位，其实验室专注于基本机制和 脑癌表观遗传学和免疫学的治疗机会。 该研究策略将研究脑中与肿瘤相关的免疫抑制性髓样细胞 肿瘤 - 它们来自哪里，它们成为的表观遗传机制 免疫抑制作用，以及如何有可能改变它们。转变或有选择地杀死 表达免疫抑制程序的髓样细胞为感官提供了绝佳的机会 脑肿瘤进行免疫疗法。但是，这些髓样细胞是否来自 循环单核细胞或内源性小胶质细胞，或使它们免疫抑制的原因， 显着阻碍了理性临床策略的设计，以靶向这些细胞在脑肿瘤中。 该提议的目的是：（1）确定免疫抑制髓样细胞的起源 脑肿瘤中的状态，（2）确定维持的表观遗传调节因素 免疫抑制细胞程序，（3）发现消除或转化的扰动 免疫抑制髓样细胞。总体而言，这些研究将提供所需的宝贵数据 开发了针对免疫抑制髓样细胞的靶向疗法并提高效率 用于脑癌患者的免疫疗法。