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

项目概要 拟议的研究职业发展计划旨在通过以下方式调查该机制： 脑肿瘤中的髓样细胞变得免疫抑制，阻止免疫系统 即使存在旨在激活肿瘤的免疫疗法，也无法控制肿瘤。的 候选人目前是马萨诸塞州病理学系的研究员 综合医院。该提案包含了以下项目所需的具体技术技能： 项目包括免疫生物学和先进免疫测定技术的培训。的 结构化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、资助写作和其他重要的职业技能。 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，并且有获得小组领导职位的学员历史 学术界以及由包括博士在内的世界级科学家组成的研究咨询委员会。 马里奥·苏瓦、约翰·伊夫拉特和尼尔·哈科恩。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 独立的医师科学家教职职位，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。 该研究策略将调查大脑中与免疫抑制肿瘤相关的骨髓细胞 肿瘤——它们来自哪里，它们变成的表观遗传机制 免疫抑制，以及如何潜在地改变它们。转化或选择性杀灭 表达免疫抑制程序的骨髓细胞提供了很好的致敏机会 脑肿瘤免疫治疗。然而，目前尚不清楚这些骨髓细胞是否来自 循环单核细胞或内源性小胶质细胞，或使它们具有免疫抑制作用的因素， 严重阻碍了针对脑肿瘤中这些细胞的合理临床策略的设计。 该提案的目的是：（1）确定免疫抑制性骨髓细胞的起源 脑肿瘤中的状态，（2）识别维持脑肿瘤的表观遗传调节因素 免疫抑制细胞程序，（3）发现消除或改变的扰动 免疫抑制性骨髓细胞。总的来说，这些研究将提供所需的有价值的数据 开发针对免疫抑制性骨髓细胞的靶向疗法并提高疗效 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.