Dissecting mechanisms of resistance underlying CD47-SIRPα inhibition in T-cell lymphomas

项目概要/摘要： ! 近年来，免疫疗法彻底改变了实体恶性肿瘤的命运， 侵袭性B细胞淋巴瘤，但T细胞淋巴瘤（TCL）仍然是孤儿。识别和封锁 CD 47-SIRPa轴的研究为研究人员利用先天免疫细胞创造了机会。 然而，来自临床试验的早期结果已经揭示，这种信号传导途径的中断不足以 通过巨噬细胞清除肿瘤细胞因此，存在未满足的需要，以确定额外的监管机构， 巨噬细胞检查点，赋予对CD 47介导的抗肿瘤应答的抗性。我最近定义了 CD 47拮抗剂诱导抗TCL反应的机制（Blood，2019）。然而，标记 TCL模型间的异质性以及CD 47表达和吞噬作用之间的不良相关性导致 我们将研究与CD 47一起或独立于CD 47控制TCL的分子机制 被巨噬细胞识别和消灭。通过结合现代下一代免疫表型分析和 单细胞测序;我将识别，机械表征，并在治疗上验证代偿性 CD 47抗性TCL模型和原始样品中的信号传导依赖性。这将奠定基础， 在TCLs中进行靶向免疫治疗的未来临床试验。 我是一名成人血液学家，在TCL拥有丰富的临床和既往研究经验，正在寻求K 08 支持达纳法伯癌症研究所（DFCI）大卫温斯托克博士实验室的指导研究， 博士大卫阿维根，贝丝以色列女执事医疗中心（BIDMC）作为共同导师。我的长期职业生涯 目标是领导一个独立的研究小组，专注于开发免疫疗法， 在一个学术癌症中心做TCL。K 08奖励将为我提供高级培训所需的受保护时间 在CD 47生物学和免疫学中，特别是大规模转录组和蛋白质组数据集分析， 实验治疗学和转化研究。我会把至少80%的时间花在 我将投入20%的精力来补充这一研究计划， 成人淋巴瘤的临床护理。Dana-Faber哈佛癌症中心（DF/HCC），由DFCI和 BIDMC是一个国际公认的研究计划，在以下领域拥有许多专家研究人员： 癌细胞生物学、免疫学和计算生物学。我召集了一个杰出的导师， 咨询委员会，由弗朗西斯Luscinskas博士，博士布鲁斯霍维茨和博士Vassiliki Bousiottis，谁将 指导我的研究和培训经验。我的咨询委员会的专业知识将得到补充， 一组额外的合作者，他们是各自领域的专家（Jim Lederer博士，Alex Shalek博士， 克里斯汀史蒂文森）。本研究提案是一个结构化计划的一部分，具有科学，技术，临床培训 和职业发展的组成部分，以确保我获得所需的专业知识，成为 一位成功的独立研究者，专注于免疫治疗和临床成人血液学。

Project Summary/Abstract: ! Over the recent years immunotherapeutic regimens have revolutionized the fate of solid malignancies and aggressive B-cell lymphomas but T-cell lymphoma (TCL) remains the orphan child. Identification and blockade of the CD47-SIRPa axis has created an opportunity for investigators to harness the innate immune cells. However early results from clinical trials have revealed that disruption of this signaling pathway is insufficient to clear tumor cells by macrophages. Thus, there is an unmet need to identify additional regulators of the macrophage checkpoint that confer resistance to CD47-mediated anti-tumor responses. I recently defined mechanisms by which CD47 antagonists induce anti-TCL response (Blood, 2019). However, marked heterogeneity across TCL models with poor correlation between CD47 expression and phagocytosis have led us to investigate molecular mechanisms that work with CD47 or independently from it in governing TCL recognition and eradication by macrophages. By combining modern next-generation immunophenotyping and single-cell sequencing; I will identify, mechanistically characterize, and therapeutically validate the compensatory signaling dependencies in CD47-resistant TCL models and primary samples. This will lay the foundation for future clinical trials of targeted immunotherapies in TCLs. I am an adult hematologist with substantial clinical and prior research experience in TCL who is seeking K08 support for mentored research in Dr. David Weinstock’s laboratory at Dana-Farber Cancer Institute (DFCI) with Dr. David Avigan, Beth Israel Deaconess Medical Center (BIDMC) acting as a co-mentor. My long-term career objective is to lead an independent research group focused on development of immunotherapy for patients with TCLs at an academic cancer center. The K08 award will provide the protected time I need for advanced training in CD47 biology and immunology, in particular, analysis of large-scale transcriptome and proteome datasets, experimental therapeutics and translational research. I will devote a minimum of 80% of my time to a focused research program on immune therapies for TCLs and will complement this with 20% of my effort dedicated to clinical care for adults with lymphomas. Dana-Faber Harvard Cancer Center (DF/HCC), comprised of DFCI and BIDMC is an internationally recognized research program with a number of expert researchers in the areas of cancer cell biology, immunology and computational biology. I have assembled an oustanding mentoring and advisory committee, consisting of Dr. Francis Luscinskas, Dr. Bruce Horwitz and Dr. Vassiliki Bousiottis, who will guide my research and training experiences. The expertise of my advisory committee will be complemented by a set of additional collaborators who are experts in their respective fields (Dr. Jim Lederer, Dr. Alex Shalek, and Kristen Stevenson). This research proposal is part of a structured plan with scientific, technical, clinical training and career development components with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on immunotherapy and clinical adult hematology.