Elucidating Human Leukemia and T Cell Interactions within the Tumor Microenvironment

阐明肿瘤微环境中人类白血病和 T 细胞的相互作用

• 批准号: 10599068
• 负责人: Pavan Bachireddy
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599068
• 关键词: Acute Myelocytic Leukemia; Address; Advisory Committees; Allogenic; Architecture; Automobile Driving; Behavior; Biological Models; Biology; Blood; Bone Marrow; Cell Communication; Cells; Chromatin; Chronic Myeloid Leukemia; Clinical; Clonality; Communities; Computational Biology; Dana-Farber Cancer Institute; Data; Development Plans; Donor Lymphocyte Infusion; Environment; Epigenetic Process; Evolution; Exhibits; Functional disorder; Gene Expression; Genetic; Genomics; Goals; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Heterogeneity; Human; Immune; Immune system; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infusion procedures; International; Leukemic Cell; Malignant Neoplasms; Maps; Mediating; Mentorship; Modeling; Molecular; Molecular Profiling; Mononuclear; Mus; Mutation; Oncogenic; Oncology; Outcome; PD-1 inhibitors; PD-1 pathway; Pathway interactions; Patients; Physicians; Population; Records; Recurrent disease; Regulation; Relapse; Research; Research Personnel; Resistance; Role; Scientist; Shapes; Stem cell transplant; Study models; System; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Testing; Therapeutic; Time; Training; Tumor Immunity; Viral; antigen-specific T cells; candidate identification; career; career development; design; epigenomics; exhaust; exhaustion; exome; functional genomics; gene regulatory network; graft vs leukemia effect; in silico; in vivo; insight; leukemia; leukemia relapse; molecular phenotype; mortality; mouse model; neoantigens; novel; post-transplant; progenitor; repaired; response; single-cell RNA sequencing; stem; transcriptome; transcriptomics; tumor; tumor microenvironment

Project Summary/Abstract Leukemic relapse remains the major obstacle to successful allogeneic stem cell transplantation (allo-SCT). Here, donor lymphocyte infusion (DLI) seeks to repair the underlying graft-versus-leukemia (GvL) effect that drives allo-SCT efficacy. However the mechanisms driving clinical GvL outcomes remain poorly understood. To address this challenge, Dr. Bachireddy has performed deep molecular phenotyping of both leukemia and immune cells within the tumor microenvironment (TME) across multiple timepoints during DLI response and resistance. He previously showed reversal of T cell exhaustion, a unique form of T cell dysfunction, during DLI response. Using high-throughput single cell RNA sequencing (scRNA-seq), he has now identified 2 main subtypes of exhausted T cells: terminally exhausted (TE) cells, enriched in pre-DLI responding TMEs, and progenitor exhausted (PE) cells, expanding consistently in responders post-DLI. While these subsets are defined in murine models of T cell exhaustion that motivated inhibitors of the PD-1 pathway, their relevance to human leukemia, roles in immunotherapeutic response, and relationship to oncogenic pathways have not been previously elucidated. Thus, he will test the hypothesis that specific gene regulatory networks (GRNs) (1) define the heterogeneity within and between TE and PE subsets and, moreover, (2) are influenced by leukemic-derived mutations and gene expression states. In Aim 1, he will determine the regulation and function of TE and PE subsets by, first, integrating scRNA-seq data with chromatin accessibility profiles to identify GRNs for each subset and then functionally evaluating the relative anti-leukemic efficacy of each subset (and each GRN) in vivo. In Aim 2, he will identify leukemic-derived molecular profiles that associate with DLI outcome and shape T/PE T cell subsets. Leukemic genomic and scRNA-seq data will be jointly analyzed to perform in silico identification of candidate leukemic drivers of DLI outcome and T/PE T cell subsets, which will, in turn, be functionally evaluated in vivo. These results will identify GRNs that govern, and oncogenic pathways that shape, TE and PE T cells, revealing novel targets for modulating cancer immunity and uncovering the molecular circuitry underpinning leukemic-immune interactions in the post-transplant TME. Dr. Bachireddy has outlined a five-year career development plan to meet his goal of becoming an independent investigator focused on immunotherapy in hematologic malignancies. He has assembled an Advisory Committee of internationally recognized experts to provide scientific/career mentorship and enlisted collaborators who are experts in computational biology, systems immunology, and functional genomics to provide experimental advice and specific training in the field. The Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard are the ideal environments for completion of his scientific and career goals, given their outstanding research communities and substantial records for training independent physician-scientists.

项目总结/摘要 白血病复发仍然是异基因造血干细胞移植（allo-SCT）成功的主要障碍。 在这里，供体淋巴细胞输注（DLI）试图修复潜在的移植物抗白血病（GvL）效应， 驱动allo-SCT的功效。然而，驱动临床GvL结果的机制仍然知之甚少。 为了应对这一挑战，Bachireddy博士对白血病和 DLI应答期间多个时间点肿瘤微环境（TME）内的免疫细胞， 阻力他先前在DLI期间显示了T细胞耗竭的逆转，这是T细胞功能障碍的一种独特形式。 反应使用高通量单细胞RNA测序（scRNA-seq），他现在已经确定了2个主要的 耗竭T细胞的亚型：终末耗竭（TE）细胞，富含前DLI应答TME，和 祖细胞耗竭（PE）细胞，在DLI后的应答者中持续扩增。虽然这些子集 在T细胞耗竭的小鼠模型中定义，其激发PD-1通路的抑制剂，它们与 人类白血病，在免疫应答中的作用，以及与致癌途径的关系还没有被 以前的解释。因此，他将测试特定基因调控网络（GRNs）的假设（1） 定义TE和PE子集内部和之间的异质性，此外，（2）受以下因素的影响 白血病衍生的突变和基因表达状态。在目标1中，他将确定 TE和PE亚群，首先，将scRNA-seq数据与染色质可及性谱整合，以识别 每个子集的GRN，然后功能性地评估每个子集的相对抗白血病功效（以及 每个GRN）。在目标2中，他将确定与DLI相关的白血病衍生分子谱 结果和形状T/PE T细胞亚群。将联合分析白血病基因组和scRNA-seq数据， 进行DLI结果和T/PE T细胞亚群的候选白血病驱动因素的计算机识别， 进而在体内进行功能评估。这些结果将确定GRNs的管理，和致癌途径 这一发现揭示了调节癌症免疫力的新靶点，并揭示了肿瘤免疫系统的作用机制。 支持移植后TME中白血病免疫相互作用的分子电路。巴奇雷迪博士 概述了一个五年职业发展计划，以实现他成为独立调查员的目标 专注于恶性血液病的免疫治疗他召集了一个咨询委员会， 国际公认的专家提供科学/职业导师和招募的合作者谁是 计算生物学、系统免疫学和功能基因组学的专家， 实地咨询和具体培训。麻省理工学院的达纳-法伯癌症研究所和布罗德研究所， 哈佛是完成他的科学和职业目标的理想环境，因为他们出色的 研究社区和大量的记录，为培训独立的医生，科学家。