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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要白血病复发仍然是成功同种异体干细胞移植（allo-SCT）的主要障碍。在这里，供体淋巴细胞输注（DLI）旨在修复潜在的移植物抗白血病（GvL）效应，提高异基因干细胞移植的疗效。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 博士对白血病和白血病进行了深度分子表型分析。 DLI 响应过程中多个时间点肿瘤微环境 (TME) 内的免疫细胞反抗。他之前在 DLI 期间展示了 T 细胞耗竭（T 细胞功能障碍的一种独特形式）的逆转回复。使用高通量单细胞 RNA 测序 (scRNA-seq)，他现已确定了 2 个主要的耗竭 T 细胞的亚型：终末耗竭 (TE) 细胞，富含 DLI 前响应 TME，以及祖细胞耗竭 (PE) 细胞在 DLI 后的反应者中持续扩增。虽然这些子集是在激发 PD-1 通路抑制剂的 T 细胞耗竭小鼠模型中定义，它们与人类白血病、免疫治疗反应中的作用以及与致癌途径的关系尚未得到证实先前已阐明。因此，他将检验特定基因调控网络 (GRN) 的假设 (1) 定义 TE 和 PE 子集内部和之间的异质性，此外，(2) 受白血病衍生的突变和基因表达状态。在目标 1 中，他将确定监管和功能首先，通过将 scRNA-seq 数据与染色质可及性图谱整合来识别 TE 和 PE 子集每个子集的 GRN，然后从功能上评估每个子集的相对抗白血病功效（以及每个GRN）在体内。在目标 2 中，他将鉴定与 DLI 相关的白血病衍生分子谱结果和形状 T/PE T 细胞亚群。白血病基因组和 scRNA-seq 数据将联合分析对 DLI 结果和 T/PE T 细胞亚群的候选白血病驱动因素进行计算机识别，这将，反过来，在体内进行功能评估。这些结果将确定控制 GRN 和致癌途径形成 TE 和 PE T 细胞，揭示了调节癌症免疫的新靶点并揭示了移植后 TME 中支持白血病-免疫相互作用的分子电路。 Bachireddy 博士有概述了五年职业发展计划，以实现成为独立调查员的目标专注于血液系统恶性肿瘤的免疫治疗。他组建了一个咨询委员会国际公认的专家提供科学/职业指导，并招募合作者计算生物学、系统免疫学和功能基因组学专家提供实验该领域的建议和具体培训。丹纳法伯癌症研究所和麻省理工学院布罗德研究所哈佛因其杰出的成就而成为他完成科学和职业目标的理想环境研究社区和培训独立医师科学家的大量记录。