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

项目摘要/摘要： 好了！ 近年来，免疫治疗方案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 CD47-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，临床试验的早期结果表明，破坏这一信号通路不足以 巨噬细胞清除肿瘤细胞。因此，有一个尚未得到满足的需求，即确定更多的监管机构 对CD47介导的抗肿瘤反应产生抵抗的巨噬细胞检查点。我最近定义了 CD47拮抗剂诱导抗TCL反应的机制(布拉德，2019)。然而，标记为 CD47表达和吞噬功能之间相关性差的TCL模型之间的异质性导致 美国将研究与CD47或独立于CD47共同作用于TCL的分子机制 巨噬细胞的识别和清除。通过将现代下一代免疫表型和 单细胞测序；我将确定，机械特征，并在治疗上验证补偿 CD47抗性TCL模型和初级样本中的信号依赖性。这将为以下工作奠定基础 TCL靶向免疫治疗的未来临床试验。 我是一名成年血液学家，在TCL有丰富的临床和既往研究经验，正在寻找K08 支持大卫·温斯托克博士在达纳-法伯癌症研究所(DFCI)的实验室进行的指导性研究 贝丝以色列女执事医疗中心(BIDMC)的David Avigan博士担任共同导师。我长期的职业生涯 目标是领导一个独立的研究小组，专注于为慢性支气管炎患者开发免疫疗法 一家学术癌症中心的TCL。K08奖将为我提供高级培训所需的保护时间 在CD47生物学和免疫学，特别是大规模转录组和蛋白质组数据集的分析中， 实验治疗学和转化研究。我会将至少80%的时间投入到一个专注的 TCL的免疫疗法研究计划，并将用我20%的努力来补充 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项目，在以下领域拥有多名专家研究人员 癌细胞生物学、免疫学和计算生物学。我已经召集了一位杰出的导师 咨询委员会，由弗朗西斯·卢辛斯卡斯博士、布鲁斯·霍维茨博士和瓦西利基·布西奥蒂斯博士组成，他将 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以下补充 一组其他合作者，他们是各自领域的专家(Jim Leder博士、Alex Shalek博士和 克里斯汀·史蒂文森)。本研究方案是科学、技术、临床培训的结构化计划的一部分。 和职业发展部分，目标是确保我获得成为 一位成功的独立研究人员，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.