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

项目总结 意义：目前可用于治疗恶性血液病的药物治疗，包括多发性 骨髓瘤(MM)和髓系白血病尽管正在进行治疗，但往往无法根除所有恶性细胞， 导致建立治疗--永久性残留病TPRD(通常被称为“最小”残留物 疾病，MRD)，它是最终患者复发的蓄水池。尽管TPRD/MRD的关键作用 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， 一直没有得到充分的研究。初步数据：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药物持续存在 通过非遗传性(在停药后可逆)低Myc肿瘤细胞状态的转录治疗 类似于胚胎滞育的变化，这是一种应激诱导的暂停发育的休眠阶段 物种。在这些研究的同时，我们的合作实验室通过CRISPR和汇集的酚类表征了 典型研究，治疗反应与耐药的分子决定因素--单纯实体瘤或血液 肿瘤细胞向自然杀伤(NK)细胞转化；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。这些研究发现了几个以前不够准确的- 化疗初期肿瘤细胞中NK细胞反应的调节因子；并观察到 临床对免疫检查点抑制剂的耐药性与治疗中NK细胞反应的特征重叠- 幼稚的肿瘤细胞，表明调节NK和细胞毒性T淋巴细胞反应的机制是正交的。不是的- 可喜的是，具有胚胎滞育样(EDL)化疗持续性的TPRD/MRD肿瘤细胞表现出复杂的Het-Het 治疗初治肿瘤细胞中与NK细胞耐药相关的转录物的性源性失调。我们 假设细胞毒性药物-持久性残留MM或白血病细胞经常表现出 对于治疗-幼稚细胞，对NK细胞细胞毒活性的不同反应模式，以及 既有共同的和不同的机制来规范这些反应。方法：以我们的经验为基础 通过对初治肿瘤细胞对NK细胞耐药性的研究和对残留病变的实验模型的研究，探讨了NK细胞耐药机制。 轻松，我们将(1)确定定义对NK细胞的应答与抵抗的基因组因素 骨髓瘤和髓系白血病细胞坚持细胞毒性药物治疗。我们还将(2) 明确TPRD肿瘤细胞-NK细胞相互作用过程中诱导的适应性分子变化及其特性。 描述它们的功能影响。新颖性-影响：通过关注未被充分研究的TPRD/MRD生物学，这篇文章 该项目将为如何为MM或AML开发基于NK细胞的个性化治疗提供新的见解 对细胞毒性药物的坚持。

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.