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

项目摘要 拟议的研究职业发展计划旨在调查的机制， 脑肿瘤中的髓样细胞具有免疫抑制作用， 即使在免疫疗法的存在下，也无法控制肿瘤。 候选人目前是马萨诸塞州病理学系的研究员 综合医院建议书中包含了执行《公约》所需的具体技术技能， 项目包括免疫生物学和先进免疫分析技术的培训。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，研究沟通，资助写作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， 他将担任主要导师，并有获得组长职位的受训者的历史 在学术界，以及研究咨询委员会的字级科学家，包括博士。 马里奥苏瓦，约翰Iafrate，和尼尔Hacohen。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，使他能够过渡到一个 独立的医生科学家教师职位，实验室专注于基本机制， 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免疫抑制性肿瘤相关髓样细胞 肿瘤-它们来自哪里，它们成为肿瘤的表观遗传机制 免疫抑制，以及如何潜在地转化它们。转化或选择性杀人 表达免疫抑制程序的骨髓细胞提供了很好的机会， 脑肿瘤的免疫治疗然而，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， 这严重阻碍了设计合理的临床策略来靶向脑肿瘤中的这些细胞。 本研究的目的是：（1）确定免疫抑制性髓系细胞的来源 （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 免疫抑制骨髓细胞。总的来说，这些研究将提供所需的宝贵数据， 开发针对免疫抑制性骨髓细胞的靶向疗法， 免疫疗法的最新进展。

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.