Mechanisms of natural killer cell resistance of treatment-persistent residual tumor cells in hematologic malignancies

血液系统恶性肿瘤中持续治疗残留肿瘤细胞的自然杀伤细胞耐药机制

基本信息

批准号：
10564354
负责人：
Constantine S. Mitsiades
金额：
$ 40.6万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564354
关键词：
Acute Myelocytic Leukemia Apoptotic Biochemical Biology Cancer Burden Cell Communication Cell Compartmentation Cell Line Cell Therapy Cells Cessation of life Characteristics Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Complex Cytotoxic Chemotherapy Cytotoxic T-Lymphocytes Cytotoxic agent Data Defect Development Diapause Disease Outcome Disease remission Early identification Embryo Exhibits Experimental Models Future Genes Genetic Transcription Genomics Hematologic Neoplasms Hematopoietic Neoplasms Immune Immune checkpoint inhibitor Immunotherapy In Vitro Individual Investigation Knowledge Leukemic Cell Molecular Molecular Profiling Multiple Myeloma Myeloid Leukemia Natural Killer Cells Outcome Patients Pattern Pharmaceutical Preparations Pharmacotherapy Phenotype Population Pre-Clinical Model Relapse Research Residual Neoplasm Residual state Resistance Role Sampling Solid Neoplasm Stress Testing Therapeutic Transcript Writing cancer cell cancer therapy chemotherapy cytotoxic drug withdrawal experience in vivo insight leukemia myeloid leukemia cell neoplastic cell non-genetic non-genomic pharmacologic prevent response therapy resistant tumor

项目摘要

PROJECT SUMMARY Significance: Currently available pharmacological therapies for hematologic malignancies, including multiple myeloma (MM) and myeloid leukemias often fail, despite ongoing treatment, to eradicate all malignant cells, resulting in establishment of treatment-persistent residual disease TPRD (often referred to as “minimal” residual disease, MRD), which serves as a reservoir for eventual patient relapses. Despite the critical role of TPRD/MRD tumor cells as a barrier to cure, their biology and therapeutic vulnerabilities, including immune responsiveness, has remained understudied. Preliminary data: Our recent studies and preliminary data indicate that treatment- persistent cancer cells in acute myeloid leukemia (AML), MM, and solid tumors persist through cytotoxic drug treatments via a non-genetic (and reversible upon drug withdrawal) low-Myc tumor cell state with transcriptional changes resembling embryonic diapause, a stress-induced dormant stage of suspended development in many species. In parallel to these studies, our collaborating labs characterized, through CRISPR and pooled pheno- typic studies, the molecular determinants of response vs. resistance of treatment-naïve solid tumor or blood cancer cells to natural killer (NK) cells; and how NK cell-induced adaptive transcriptional changes in tumor cells may contribute to their persistence against NK cells. These studies identified several previously underappreci- ated regulators of NK cell responses in chemo-naïve tumor cells; and observed that molecular signatures of clinical resistance to immune checkpoint inhibitors overlap with signatures of NK cell response in treatment- naïve tumor cells, suggesting orthogonal mechanisms regulating NK vs. cytotoxic T lymphocyte responses. No- tably, TPRD/MRD tumor cells with embryonic diapause-like (EDL) chemopersistence exhibit complex and het- erogeneous dysregulation of transcripts associated with NK cell resistance in treatment-naïve tumor cells. We hypothesize that cytotoxic drug-persistent residual MM or leukemic cells may often exhibit, compared to treatment-naïve cells, distinct patterns of responses to the cytotoxic activity of NK cells, as well as both shared and distinct mechanisms regulating those responses. Approach: Building on our experience with studies on NK cell resistance of treatment-naïve tumor cells and with experimental models of residual dis- ease, we will (1) identify genomic factors that define responsiveness vs. resistance to NK cells using myeloma and myeloid leukemia cells persistent to cytotoxic pharmacological therapies. We will also (2) define adaptive molecular changes induced during TPRD tumor cell - NK cell interactions and charac- terize their functional impact. Novelty-Impact: By focusing on the understudied biology of TPRD/MRD, this project will provide new insights on how to develop individualized NK cell-based therapies for MM or AML with persistence to cytotoxic drugs.

项目概要意义：目前可用于治疗血液恶性肿瘤的药物疗法，包括多种尽管持续治疗，骨髓瘤（MM）和髓性白血病通常无法根除所有恶性细胞，导致治疗持续性残留病 TPRD（通常称为“最小”残留病）的建立尽管 TPRD/MRD 发挥着关键作用，但它还是最终患者复发的储存库。肿瘤细胞作为治愈的障碍，其生物学和治疗脆弱性，包括免疫反应，初步数据尚未得到充分研究：我们最近的研究和初步数据表明治疗- 急性髓系白血病 (AML)、MM 和实体瘤中的持久性癌细胞通过细胞毒性药物持续存在通过具有转录功能的非遗传性（停药后可逆）低Myc肿瘤细胞状态进行治疗类似于胚胎滞育的变化，这是许多人中应激引起的暂停发育的休眠阶段在进行这些研究的同时，我们的合作实验室通过 CRISPR 和汇集的表型来表征。典型研究，未接受治疗的实体瘤或血液的反应与耐药性的分子决定因素癌细胞到自然杀伤 (NK) 细胞；以及 NK 细胞如何诱导肿瘤细胞的适应性转录变化可能有助于它们对 NK 细胞的持久性。这些研究发现了一些以前未被充分认识的细胞。在未接受化疗的肿瘤细胞中调节 NK 细胞反应，并观察到 NK 细胞的分子特征；对免疫检查点抑制剂的临床耐药性与治疗中 NK 细胞反应的特征重叠幼稚肿瘤细胞，表明调节 NK 与细胞毒性 T 淋巴细胞反应的正交机制。显然，具有胚胎滞育样（EDL）化学持久性的 TPRD/MRD 肿瘤细胞表现出复杂和异质性。与未接受治疗的肿瘤细胞中的 NK 细胞耐药性相关的转录物的性感失调。相比之下，细胞毒性药物持续残留的 MM 或白血病细胞可能经常表现出对于未经治疗的细胞，对 NK 细胞的细胞毒活性的不同反应模式，以及规范这些应对措施的共同机制和独特机制：以我们的经验为基础。通过对未接受过治疗的肿瘤细胞的 NK 细胞耐药性以及残余放电实验模型的研究，轻松地，我们将 (1) 使用以下方法确定定义对 NK 细胞的反应性与耐药性的基因组因素：骨髓瘤和骨髓性白血病细胞对细胞毒性药物治疗持续存在（2）。定义 TPRD 肿瘤细胞 - NK 细胞相互作用和特征期间诱导的适应性分子变化新颖性影响：通过关注 TPRD/MRD 的未充分研究的生物学，这该项目将为如何开发针对 MM 或 AML 的个体化 NK 细胞疗法提供新见解对细胞毒性药物的持久性。