Monocyte promotion of therapy resistance by immune and non-immune mechanisms

单核细胞通过免疫和非免疫机制促进治疗抵抗

• 批准号: 9762055
• 负责人: Yi Lin
• 金额: $ 35.28万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762055
• 关键词: Agonist; Animal Model; Antibody Therapy; Antisense Oligonucleotides; Automobile Driving; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Biological Response Modifiers; CD14 gene; Cancer Patient; Cell physiology; Cells; Cellular Stress; Clinical; Clinical Trials; Data; Dendritic Cells; Development; Disease Progression; Doxorubicin; Drug Delivery Systems; Glioblastoma; Goals; HLA-DR Antigens; Hematologic Neoplasms; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Infection; Liposomes; Lymphoma; Malignant Neoplasms; Mediating; Modeling; Molecular; Morbidity - disease rate; Myelogenous; Myeloid-derived suppressor cells; Nomenclature; Outcome; PD-1/PD-L1; Patients; Phenotype; Play; Population; Prognostic Marker; Renal Cell Carcinoma; Reporting; Research Personnel; Resistance; Role; SLEB2 gene; Sampling; Signal Pathway; Signal Transduction; Solid Neoplasm; T-Lymphocyte; TLR7 gene; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Immunity; Vascular Endothelium; Wound Healing; anti-PD1 antibodies; base; cancer therapy; cancer type; chemotherapy; clinical development; cytokine; cytotoxic; immune function; immune resistance; improved; in vitro Model; innovation; large cell Diffuse non-Hodgkin' s lymphoma; liposomal delivery; monocyte; neoplastic cell; novel; peripheral blood; personalized medicine; phase II trial; prognostic significance; public health relevance; response; targeted treatment; therapeutic target; therapy design; therapy development; therapy resistant; transcriptome; treatment response; treatment strategy; tumor; tumor microenvironment; tumor xenograft

Abstract Immunotherapies such as checkpoint inhibitors have demonstrated exciting clinical responses in the recent years, demonstrating the important role of host immune system in cancer. We were the first group to report a novel population of immunosuppressive monocytes, characterized by a loss of HLA-DR expression (CD14+HLA-DRlow/neg), in lymphoma, renal cell carcinoma, glioblastoma multiforme and other cancer types. These cells are PD-1 positive in lymphoma tumors. We have characterized the suppressive functions of these cells on systemic immunity and demonstrated correlation of these cells to decreased PFS and OS. Other researchers have reported corroborative findings in other cancer types. While many in the field have termed these cells as monocytic myeloid derived suppressor cells (MDSC) based on their immune functions, we have also identified immune independent mechanism by which these cells directly promote chemo-resistance in lymphoma. Therefore we believe that these cells have a broader spectrum of functions than MDSC and have defined them as regulatory monocytes, Mreg. Our central hypothesis is that lymphoma tumor and Mreg croos talk is a key mechanism that leads to suppression of anti-lymphoma immunity and chemotherapy resistance, thereby, reducing survival. In this R01 proposal, we will examine Mreg lymphoma crosstalk that promotes treatment resistance and identify potential therapeutic strategies. This will be achieved through three specific aims: 1) Identify the mechanisms of Mreg mediated lymphoma resistance to chemotherapy, specifically focusing on Hsp27 signaling. Animal model will be developed to examine Mreg lymphoma interaction in chemo-resistance, including primary patient tumor xenografts and testing of Apatorsen, an anti-sense oligonucleotide that inhibits Hsp27 in clinical trial development for solid tumors. 2) Examine strategies to reprogram Mreg to improve anti-lymphoma immunity, specifically testing blockade of Hsp27 and PD-1/PD-L1/L2 in lymphoma Mreg crosstalk and stimulation with toll-like receptor-7 (TLR7) agonist. In addition we will examine a novel liposome-packaged drug delivery system to target Mreg. 3) Identify the prognostic significance of intra-tumor Mreg. Completion of Aims 1 and 2 will identify more than one potential treatment strategies targeting Mreg lymphoma crosstalk for clinical trial development. Completion of Aim 3 will assist the development of a personalized therapy approach where patients with high levels intra-tumor Mreg will receive therapy targeting Mreg lymphoma crosstalk.

抽象的 诸如检查点抑制剂之类的免疫疗法在最近显示出令人兴奋的临床反应 几年，证明了宿主免疫系统在癌症中的重要作用。我们是第一个报告 新型免疫抑制单核细胞，其特征是HLA-DR表达的丧失 （CD14+HLA-DRLOW/NEG），淋巴瘤，肾细胞癌，多形胶质母细胞瘤和其他癌症类型。 这些细胞在淋巴瘤肿瘤中为PD-1阳性。我们已经表征了这些的抑制作用 细胞具有全身免疫力，并证明了这些细胞与PFS和OS降低的相关性。其他 研究人员报告了其他癌症类型的佐证发现。虽然该领域的许多人称为 这些细胞是基于其免疫功能的单核细胞髓样衍生抑制细胞（MDSC），我们有 还确定了免疫独立机制，这些机制通过这些机制直接促进化学抗性 淋巴瘤。因此，我们认为这些细胞比MDSC具有更广泛的功能范围，并且具有 将它们定义为调节单核细胞Mreg。我们的中心假设是淋巴瘤肿瘤和MREG CROO Talk是一种关键机制，可导致抗淋巴瘤免疫力和 化学疗法抗性，从而降低生存率。在此R01提案中，我们将检查MREG 淋巴瘤串扰，可促进治疗耐药性并确定潜在的治疗策略。这会 可以通过三个特定目的来实现：1）确定MREG介导的淋巴瘤的机制 对化学疗法的耐药性，特别关注HSP27信号传导。动物模型将开发到 检查化学抗性中的MREG淋巴瘤相互作用，包括原发性肿瘤异种移植物和 Apatorsen测试是一种抗沉思寡核苷酸，抑制HSP27的临床试验开发中的HSP27 肿瘤。 2）检查重新编程MREG以提高抗淋巴瘤免疫力的策略，特别是 在淋巴瘤MREG串扰中对HSP27和PD-1/PD-L1/L2的测试阻塞，并用Toll样刺激 受体-7（TLR7）激动剂。此外，我们将检查一种新型的脂质体包装的药物输送系统 目标MREG。 3）确定肿瘤内MREG的预后意义。目标1和2将 确定针对MREG淋巴瘤串扰进行临床试验的多种潜在治疗策略 发展。 AIM 3的完成将有助于开发一种个性化的治疗方法 高肿瘤内MREG的患者将接受针对MREG淋巴瘤串扰的治疗。