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

项目总结 拟议的研究职业发展计划试图通过以下方式调查这一机制 脑瘤中的哪些髓系细胞会产生免疫抑制作用，从而阻止免疫系统 即使在旨在激活肿瘤的免疫疗法存在的情况下也无法控制肿瘤。这个 候选人目前是马萨诸塞州病理学系的研究员 综合医院。该提案包含了以下方面所需的特定技术技能 项目包括免疫生物学和高级免疫检测技术方面的培训。这个 有组织的职业发展计划包括实验室管理方面的培训和指导， 科学领导力、研究交流、拨款撰写和其他关键的职业技能。 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，并有获得组长职位的受训人员的历史 在学术界，以及由世界一流的科学家组成的研究咨询委员会。 马里奥·苏瓦、约翰·拉夫拉特和尼尔·哈科恩。通过这一全面的计划，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 独立的内科科学家教员职位，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。 该研究战略将研究大脑中免疫抑制的肿瘤相关髓系细胞 肿瘤--它们从哪里来，它们形成的表观遗传机制 免疫抑制，以及如何潜在地改变它们。转变或选择性地杀死 表达免疫抑制程序的髓系细胞提供了极大的机会来敏化 脑瘤到免疫治疗。然而，目前尚不清楚这些髓系细胞是否来自 循环中的单核细胞或内源性小胶质细胞，或者是什么使它们具有免疫抑制作用， 显著阻碍了设计合理的临床策略来靶向脑肿瘤中的这些细胞。 这项建议的目的是：(1)确定免疫抑制髓系细胞的来源 脑肿瘤的状态，(2)确定维持脑肿瘤的表观遗传调节因子 免疫抑制细胞程序，(3)发现消除或转化的扰动 免疫抑制的髓系细胞。总体而言，这些研究将提供所需的宝贵数据 开发针对免疫抑制髓系细胞的靶向治疗并提高疗效 针对脑癌患者的免疫治疗。

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.