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

• 批准号: 10682439
• 负责人: Fotios Asimakopoulos
• 金额: $ 50.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10682439
• 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; Cell secretion; Cells; Coupled; Cytometry; Dendritic Cells; Distal; Eligibility Determination; Engraftment; 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; Infiltration; Interleukin-10; Investigation; Knowledge; Lentivirus Vector; Ligands; MEKs; Macrophage; Maintenance; Mediating; Modeling; Multiple Myeloma; Mutate; Myelogenous; Myeloid Cells; 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; cell growth; cytokine; design; experimental study; extracellular; immunoregulation; in vivo; inhibitor; lenalidomide; macromolecule; molecular targeted therapies; neutralizing antibody; novel; paracrine; polarized cell; prevent; relapse patients; relapse prevention; response; standard of care; success; therapeutic target; transplantation therapy; treatment strategy; tumor; versican

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.

项目总结/摘要 多发性骨髓瘤（MM）是第二大最常见的血液癌症，并且仍然无法治愈。自体 干细胞移植（ASCT）仍然是适合患者的主要治疗方法。尽管常规使用 新药物作为ASCT后“维持”以延迟或预防复发，大多数患者将在ASCT后死亡。 移植有大量证据表明，免疫调节机制的建立 在ASCT后骨髓（BM）微环境中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IL 10的骨髓细胞（树突状细胞（DC）和巨噬细胞， 统称为tol-DC）和IL 17被提出以细胞自主的方式作用于MM细胞。然而，在这方面， 引发这些过程的上游信号或微环境触发因素尚不清楚。 通过Toll样受体（TLR）-2信号传导促进Tol-DC极化和Th 17分化。我们 先前报道MM-辅助细胞分泌TLR 2-配体基质蛋白聚糖，多功能蛋白聚糖（VCAN）。 VCAN促进癌中的tol-DC极化，因此，它构成了触发癌的主要嫌疑人。 复发促进，TLR 2依赖的过程中MM。 在MM微环境中，特别是ASCT后，VCAN经历ADAMTS介导的细胞外 蛋白水解以释放N-末端片段versikine。Versikine作为matrikine（细胞外基质- 通常以不同于其母体大分子的方式调节细胞活性的衍生片段）。 Versikine是弱的IL 6/IL 10触发剂，因此它不太可能是有效的tol-DC/Th 17诱导剂。相反，versikine 在体外和体内刺激IRF 8依赖性转录物并促进IRF 8依赖性Batf 3-DC亚群。 我们假设versikine-IRF 8-Batf 3-DC轴可能与强效（也许是显性） 耐受原性VCAN-TLR 2途径中的动态串扰。 我们有两个具体的目的来研究VCAN和versikine调节抗- ASCT后MM免疫：在目标1中，我们将剖析抗MM免疫中的VCAN-TLR 2信号传导，并设计 基于靶向致耐受性VCAN-TLR 2信号传导的新型ASCT后治疗策略。在目标2中， 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后生存期。的 我们最近提出的第一代Ras驱动的MM模型VQ促进了这里提出的实验。Ras 途径是人MM中最常见的突变途径。与目前最先进的MM模型相反， 在C57 BL/6 J受体中，VQ容易被慢病毒载体和移植物转导（促进VQ在C57 BL/6 J受体中的机制）。 体内研究）。这里提出的一些研究已经不可能或不切实际使用现有的MM 模型

项目成果

Proceedings from the Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Immune and Cellular Therapy in Multiple Myeloma.

• DOI: 10.1016/j.jtct.2022.05.019
• 发表时间: 2022-08
• 期刊: TRANSPLANTATION AND CELLULAR THERAPY
• 影响因子: 3.2
• 作者: Holstein, Sarah A.;Asimakopoulos, Fotis;Azab, Abdel Kareem;Bianchi, Giada;Bhutani, Manisha;Crews, Leslie A.;Cupedo, Tom;Giles, Hannah;Gooding, Sarah;Hillengass, Jens;John, Lukas;Kaiser, Shari;Lee, Lydia;Maclachlan, Kylee;Pasquini, Marcelo C.;Pichiorri, Flavia;Shah, Nina;Shokeen, Monica;Shy, Brian R.;Smith, Eric L.;Verona, Raluca;Usmani, Saad Z.;McCarthy, Philip L.
• 通讯作者: McCarthy, Philip L.

Emerging roles for tumor stroma in antigen presentation and anti-cancer immunity.

• DOI: 10.1042/bst20221083
• 发表时间: 2023-12-20
• 期刊: Biochemical Society transactions
• 影响因子: 3.9

Molecular characterization stratifies VQ myeloma cells into two clusters with distinct risk signatures and drug responses.

• DOI: 10.1038/s41388-023-02684-9
• 发表时间: 2023-05
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Flietner, Evan;Yu, Mei;Poudel, Govinda;Veltri, Anthony J. J.;Zhou, Yun;Rajagopalan, Adhithi;Feng, Yubin;Lasho, Terra;Wen, Zhi;Sun, Yuqian;Patnaik, Mrinal M. M.;Callander, Natalie S. S.;Asimakopoulos, Fotis;Wang, Demin;Zhang, Jing
• 通讯作者: Zhang, Jing