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

项目摘要 意义：目前可用的血液恶性肿瘤药物治疗，包括多种 骨髓瘤（MM）和髓性白血病尽管进行治疗，但通常不能根除所有恶性细胞， 导致建立治疗持续性残留疾病TPRD（通常称为“最小”残留 疾病，MRD），其作为最终患者复发的储存库。尽管贸易和农村发展司/监测和研究司发挥了关键作用， 肿瘤细胞作为治愈的屏障，它们的生物学和治疗弱点，包括免疫反应性， 一直未被充分研究初步数据：我们最近的研究和初步数据表明，治疗- 急性髓性白血病（AML）、MM和实体瘤中的持续性癌细胞通过细胞毒性药物 通过非遗传性（并且在药物停药后可逆）低Myc肿瘤细胞状态与转录抑制剂治疗， 类似于胚胎滞育的变化，在许多动物中， 物种在这些研究的同时，我们的合作实验室通过CRISPR和合并的表型特征， 典型研究，初治实体瘤或血液肿瘤的缓解与耐药的分子决定因素 癌细胞向自然杀伤（NK）细胞转化;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。这些研究确定了一些以前不太重视的问题， 在未经化疗的肿瘤细胞中，NK细胞反应的调节因子;并观察到， 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淋巴细胞应答的正交机制。不，不，不 值得注意的是，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， 在未经治疗的肿瘤细胞中与NK细胞抗性相关的转录物的雌激素性失调。我们 假设细胞毒性药物持续残留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反应模式不同，以及 这两个共同的和独特的机制调节这些反应。方法：基于我们的经验 通过对未经治疗的肿瘤细胞的NK细胞耐药性的研究和残留病灶的实验模型， 我们将（1）确定基因组因素，定义对NK细胞的反应性与抗性， 骨髓瘤和骨髓性白血病细胞对细胞毒性药物治疗的耐受性。我们也将（2） 定义TPRD肿瘤细胞- NK细胞相互作用期间诱导的适应性分子变化和特征， 其功能影响。新颖性影响：通过关注TPRD/MRD的未充分研究的生物学， 该项目将为如何开发基于NK细胞的MM或AML个体化疗法提供新的见解， 对细胞毒性药物的持久性。

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.