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

• 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
• 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

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.

项目摘要 意义：目前可用于血液系统恶性肿瘤的药物疗法，包括多个 骨髓瘤（MM）和髓样白血病经常失败，目的地正在进行治疗，可以放射所有恶性细胞， 导致建立治疗性残留疾病TPRD（通常称为“最小”残留 疾病，MRD），它是事件患者复发的储层。尽管TPRD/MRD的作用至关重要 肿瘤细胞作为治愈的障碍，它们的生物学和治疗脆弱性，包括免疫反应性， 仍然了解。初步数据：我们最近的研究和初步数据，表明治疗 - 急性髓样白血病（AML），MM和实体肿瘤中的持续性癌细胞通过细胞毒性药物持续存在 通过转录的非遗传（可逆）低m-myc肿瘤细胞态治疗 变化类似于胚胎滞育，这是压力引起的休眠阶段的悬浮发育的休眠阶段 物种。与这些研究并行，我们的合作实验室通过CRISPR和合并的现场表征 典型研究，反应的分子决定剂与未经治疗的固体瘤或血液的抗性 癌细胞到天然杀手（NK）细胞；以及NK细胞诱导的肿瘤细胞的适应性转录变化 可能有助于他们对NK细胞的持久性。这些研究确定了几个先前未被评估的 NK细胞反应的ATED调节剂在没有化学的肿瘤细胞中；并观察到分子特征 对免疫切除点抑制剂的临床抵抗与治疗中NK细胞反应的特征重叠 - 幼稚的肿瘤细胞，表明正交机制调节NK与细胞毒性T淋巴细胞反应。不- Tably，TPRD/MRD肿瘤细胞具有胚胎性肿瘤样（EDL）化学症提取物复合物和HET- 在没有治疗的肿瘤细胞中与NK细胞耐药性相关的转录本的异构失调。我们 假设细胞毒性药物抗性残留MM或白血病细胞可能经常表现出来 对于未经治疗的细胞，对NK细胞的细胞毒性活性的不同反应模式以及 共享和不同的机制来调节这些反应。方法：基于我们的经验 通过研究未经治疗的肿瘤细胞的NK细胞耐药性以及残余疾病的实验模型 轻松，我们将（1）确定使用反应能力与使用NK细胞的抗性的基因组因子 骨髓瘤和髓样白血病细胞持续进行细胞毒性药物疗法。我们也将（2） 定义在TPRD肿瘤细胞 - NK细胞相互作用和特征中诱导的适应性分子变化 构成其功能影响。新颖性影响：通过关注TPRD/MRD的知识生物学， 项目将提供有关如何使用MM或AML开发个性化基于NK细胞的疗法的新见解。 对细胞毒性药物的持久性。