Tumor matrix remodeling in anti-myeloma immunity and immunotherapy

抗骨髓瘤免疫和免疫治疗中的肿瘤基质重塑

基本信息

批准号：
10037366
负责人：
Fotios Asimakopoulos
金额：
$ 52.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10037366
关键词：
ADAMTS Address Amino Acids Antibodies Antigen-Presenting Cells Autologous Stem Cell Transplantation Avian Leukosis Virus Binding Bone Marrow Bone Marrow Stem Cell Transplantation CRISPR/Cas technology Carcinoma Cell Density Cells Coupled Cytometry Dendritic Cells Distal Equilibrium Extracellular Matrix FDA approved FLT3 ligand Generations Goals Hematologic Neoplasms Hematopoietic Neoplasms Human IL17 gene IL6 gene Immune Immunity Immunologics Immunomodulators Immunotherapy In Vitro Inferior Interleukin-10 Investigation Knowledge Lentivirus Vector Ligands MEKs Maintenance Mediating Modeling Multiple Myeloma Mutate Myelogenous Myeloid Cells Myeloproliferative disease N-terminal Oral Parents Pathway interactions Patients Physiological Process Protein Isoforms Proteoglycan Proteolysis Regulatory Pathway Relapse Reporting Resolution Revlimid Role Safety Signal Transduction Site TLR2 gene Testing Thalidomide Therapeutic Transcript Transplantation Vertebral column adverse outcome analog base cell growth cytokine design experimental study extracellular immunoregulation in vivo inhibitor/antagonist lenalidomide macromolecule macrophage molecular targeted therapies neutralizing antibody novel paracrine polarized cell prevent relapse patients response standard of care success therapeutic target treatment strategy tumor versican

项目摘要

PROJECT SUMMARY/ ABSTRACT Multiple myeloma (MM) ranks as the second most common blood cancer and it remains incurable. Autologous stem cell transplantation (ASCT) remains a mainstay of therapy for eligible patients. Despite the routine use of novel agents as post-ASCT “maintenance” to delay or prevent relapse, most patients will succumb after transplant. There is considerable body of evidence to suggest that immunoregulatory mechanisms established in post-ASCT bone marrow (BM) microenvironment favor relapse and constitute attractive therapeutic targets. Post-ASCT relapses depend on tolerogenic IL10-producing myeloid cells (dendritic cells (DC) and macrophages, collectively referred to as tol-DC) and IL17 proposed to act on MM cells in a cell-autonomous manner. However, the upstream signals or microenvironmental triggers that elicit these processes are unclear. Tol-DC polarization and Th17 differentiation are promoted through Toll-like receptor (TLR)-2 signaling. We previously reported that MM-accessory cells secrete the TLR2-ligand matrix proteoglycan, versican (VCAN). VCAN promotes tol-DC polarization in carcinomas and therefore, it constitutes a prime suspect for triggering relapse-promoting, TLR2-dependent processes in MM. In the MM microenvironment, specifically post-ASCT, VCAN undergoes ADAMTS-mediated extracellular proteolysis to release an N-terminal fragment, versikine. Versikine acts as a matrikine (an extracellular matrix- derived fragment that regulates cell activity, often in a manner distinct from that of its parent macromolecule). Versikine is a weak IL6/IL10 trigger, therefore it is unlikely to be a potent tol-DC/Th17 inducer. Instead, versikine stimulates IRF8-dependent transcripts and promotes the IRF8-dependent Batf3-DC subset in vitro and in vivo. We hypothesize that the versikine-IRF8-Batf3-DC axis may engage the potent (and perhaps dominant) tolerogenic VCAN-TLR2 pathway in a dynamic crosstalk. We have delineated 2 specific Aims to investigate the mechanisms by which VCAN and versikine regulate anti- MM immunity post-ASCT: In Aim 1, we shall dissect VCAN-TLR2 signaling in anti-MM immunity and design novel post-ASCT treatment strategies based on targeting tolerogenic VCAN-TLR2 signaling. In Aim 2, we shall study in-depth the role of the matrikine, versikine, in anti-MM immunity. Success of our Aims will optimize MM treatment (maintenance) strategies to prolong post-ASCT survival. The experiments proposed here are facilitated by our recent generation of the first Ras-driven MM model, VQ. RAS pathway is the most commonly mutated pathway in human MM. In contrast to current state-of-art MM models, VQ is readily transducible by lentiviral vectors and engrafts in C57BL/6J recipients (facilitating mechanistic in vivo studies). Several of the studies proposed here have been impossible or impractical using existing MM models.

项目概要/摘要多发性骨髓瘤 (MM) 是第二常见的血液癌症，并且仍然无法治愈。尽管干细胞移植（ASCT）已被常规使用，但仍然是符合条件的患者的主要治疗方法。新型药物作为 ASCT 后“维持”以延缓或预防复发，大多数患者会在有大量证据表明免疫调节机制已建立。 ASCT 后骨髓 (BM) 微环境有利于复发并构成有吸引力的治疗靶点。 ASCT 后复发取决于产生耐受性 IL10 的骨髓细胞（树突状细胞 (DC) 和巨噬细胞，统称为tol-DC）和IL17建议以细胞自主的方式作用于MM细胞。引发这些过程的上游信号或微环境触发因素尚不清楚。 Tol-DC 极化和 Th17 分化通过 Toll 样受体 (TLR)-2 信号传导促进。先前报道MM辅助细胞分泌TLR2配体基质蛋白聚糖，多功能蛋白聚糖（VCAN）。 VCAN 促进癌症中的 tol-DC 极化，因此，它构成了触发的主要嫌疑人 MM 中促进复发、依赖 TLR2 的过程。在 MM 微环境中，特别是 ASCT 后，VCAN 经历 ADAMTS 介导的细胞外蛋白水解释放 N 末端片段，versikine 作为 matrikine（一种细胞外基质）。调节细胞活性的衍生片段，通常以不同于其母体大分子的方式）。 Versikine 是一种弱 IL6/IL10 触发剂，因此它不太可能是有效的 tol-DC/Th17 诱导剂。在体外和体内刺激 IRF8 依赖性转录物并促进 IRF8 依赖性 Batf3-DC 子集。我们发现 versikine-IRF8-Batf3-DC 轴可能会参与有效的（也许是主导的）动态串扰中的耐受性 VCAN-TLR2 通路。我们已经描绘了 2 个具体目标来研究 VCAN 和 versikine 调节抗- ASCT 后的 MM 免疫：在目标 1 中，我们将剖析抗 MM 免疫和设计中的 VCAN-TLR2 信号传导基于针对耐受性 VCAN-TLR2 信号传导的新型 ASCT 后治疗策略在目标 2 中，我们将实现这一目标。深入研究 matrikine、versikine 在抗 MM 免疫中的作用。我们目标的成功将优化 MM 治疗（维持）策略，以延长 ASCT 后的生存期。我们最新一代的第一个 Ras 驱动的 MM 模型 VQ 促进了此处提出的实验。途径是人类 MM 中最常见的突变途径，与当前最先进的 MM 模型相比， VQ 很容易被慢病毒载体转导并移植到 C57BL/6J 受体中（促进机制这里提出的一些研究使用现有的 MM 是不可能或不切实际的模型。