Dual targeting of tumoral microenvironment and tumoral cells by blocking the IL-33/ST2 pathway

通过阻断 IL-33/ST2 通路双重靶向肿瘤微环境和肿瘤细胞

• 批准号: 10228863
• 负责人: NAI-KONG V CHEUNG
• 金额: $ 15.31万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-06 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228863
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adult; Allogenic; Annual Reports; Antibodies; Biological; Biology; Bispecific Antibodies; Bone Marrow; Brain Neoplasms; CAR T cell therapy; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells; Childhood Solid Neoplasm; Data; Defect; Development; FOXP3 gene; Goals; Human; IgG1; Immune; Immunity; Immunocompetent; Immunotherapy; Interferon Type II; Interferons; Interleukin-2; Interleukins; Knock-out; Knowledge; Lead; Leukemic Cell; Liquid substance; Lymphocyte; MLL-AF9; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Membrane; Memorial Sloan-Kettering Cancer Center; Modeling; Molecular; Mus; NCI Center for Cancer Research; Nature; Neuroblastoma; Non-Malignant; Pathway interactions; Patients; Pediatric Neoplasm; Population; Process; Proteome; Regimen; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Soft tissue sarcoma; Solid; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Tissue Banks; Tumor Immunity; Tumor-infiltrating immune cells; Wild Type Mouse; Work; Xenograft Model; Xenograft procedure; acute myeloid leukemia cell; base; chemotherapy; cytotoxic; exhaustion; experimental study; hematopoietic cell transplantation; high throughput screening; humanized mouse; in vivo Model; innovation; insight; irradiation; leukemia; leukemia/lymphoma; mouse model; neoplastic cell; neutralizing antibody; novel; osteosarcoma; overexpression; personalized medicine; public health relevance; receptor; response; restoration; sarcoma; standard care; transcriptome; treatment planning; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; unpublished works; virtual

PROJECT SUMMARY/ABSTRACT: A fundamental gap exists in our knowledge of the immunologic tumoral microenvironment during the development of acute myeloid leukemia (AML) and other deadly childhood cancers. Bridging of this gap could lead to novel immunotherapies. Our long-term goals are to develop novel immunotherapies for leukemia and pediatric solid tumors. Our objective in this application is to investigate the role of Foxp3+ regulatory T cells (Tregs) expressing Stimulation-2 (ST2), the IL-33 receptor in the microenvironment as well as ST2 on tumoral cells. Our central hypothesis is that we can target the tumoral microenvironment and tumoral cells by blocking the IL-33/ST2 pathway with neutralizing and bispecific antibodies that we will develop. This hypothesis was formed based on our unpublished preliminary data showing that: First, nonmalignant mice deficient in T-bet have elevated numbers of BM-infiltrating ST2+ Tregs compared to wild-type (WT) mice (45% vs 25%, respectively), suggesting reciprocal roles of ST2/IL33 and T- bet/interferon-γ (IFN-γ) in Tregs from the BM niche. Second, we observed 10-fold more Tregs expressing significantly more activation markers in the BM niche of AML-bearing mice than in the nonmalignant niche. Third, MLL-AF9 AML cell proliferation was significantly lower in mice receiving donor syngeneic ST2 knock-out (ST2-/-) T cells than in mice receiving donor syngeneic WT T cells (2% vs 17%, respectively). ST2 blockade also decreased Treg activation (i.e., KLRG1) and increased type 1 signaling in CD8+ T cells as well as decreased their exhaustion, suggesting restoration of an antitumoral response in ST2-/- mice. The rationale for this study is that once we are able to understand the biology of the immunological microenvironment in the malignant niche, we can propose personalized treatment plans to block the tolerogenic pathways. Similarly, understanding the biology responsible for the overexpression of ST2/IL-33 on the tumoral cell, will help target this pathway. This hypothesis will be tested with three specific aims: 1) Explore ST2 and IL-33 expression on tumoral cells and in the tumoral microenvironment from liquid and solid childhood cancers in human and mice; 2) Examine whether ST2/IL-33 blockade can impact tumor immunity in the malignant BM niche and solid tumor microenvironment as a proof-of-principle of a novel antitumoral immunotherapy; and 3) Optimizing anti-ST2 neutralizing antibodies against murine and human targets for translational purpose. This approach is innovative because, to our knowledge, the function of ST2+ Tregs in the malignant microenvironment, remains virtually unexplored. It will also provide biological insights into the nature of ST2+ Tregs and ST2+ tumoral cells in the microenvironment and determine whether their blockade can restore antitumoral activity and decrease tumoral proliferation via a dual mechanism. The proposed research is significant because novel antitumoral immunotherapies that are more targeted and less toxic than classical chemotherapy/irradiation regimens are needed.

项目总结/摘要：我们对免疫肿瘤的认识存在根本性的差距。 急性髓细胞白血病（AML）和其他致命的儿童期发展过程中的微环境 癌的弥合这一差距可能会导致新的免疫疗法。我们的长期目标是开发新的 白血病和儿科实体瘤的免疫疗法。本申请的目的是调查 表达IL-33受体Stimulation-2（ST 2）的Foxp 3+调节性T细胞（Tregs）在肿瘤中的作用 微环境以及肿瘤细胞上的ST 2。我们的核心假设是我们可以靶向肿瘤 通过用中和性和双特异性抗体阻断IL-33/ST 2通路， 我们将开发的抗体。这一假设是根据我们未发表的初步数据形成的 表明：首先，T-bet缺陷的非恶性小鼠骨髓浸润性ST 2+调节性T细胞数量增加 与野生型（WT）小鼠相比（分别为45%和25%），表明ST 2/IL 33和T- bet/干扰素-γ（IFN-γ）在来自BM小生境的Tcells中的表达。第二，我们观察到10倍以上的TcR表达， 在AML小鼠的BM生态位中比在非恶性生态位中显著更多的活化标志物。 第三，MLL-AF 9 AML细胞增殖在接受供体同基因ST 2敲除的小鼠中显著降低 (ST2-/-）T细胞的比例高于接受供体同基因WT T细胞的小鼠（分别为2%对17%）。ST 2阻滞 也降低了Treg活化（即，KLRG 1）和增加CD 8 + T细胞中的1型信号传导以及 降低了它们的疲劳，表明恢复了ST 2-/-小鼠的抗肿瘤反应。的理由 这项研究是，一旦我们能够了解免疫微环境的生物学， 恶性小生境，我们可以提出个性化的治疗计划，以阻止耐受性途径。同样地， 了解ST 2/IL-33在肿瘤细胞上过度表达的生物学机制，将有助于靶向 这条路。将用三个具体目的来检验该假设：1）探索ST 2和IL-33表达， 肿瘤细胞和来自人类和小鼠的液体和固体儿童癌症的肿瘤微环境; 2)检查ST 2/IL-33阻断是否可以影响恶性BM龛和实体瘤中的肿瘤免疫 微环境作为一种新的抗肿瘤免疫疗法的原理证明;和3）优化抗ST 2 用于翻译目的的针对鼠和人靶标的中和抗体。这种做法是创新的 因为，据我们所知，ST 2 + T细胞在恶性微环境中的功能， 未开发的它还将为研究中ST 2 + Tregs和ST 2+肿瘤细胞的性质提供生物学见解 微环境，并确定它们的阻断是否可以恢复抗肿瘤活性和减少肿瘤微环境。 通过双重机制扩散。这项研究具有重要意义，因为新的抗肿瘤药物 比传统化疗/放疗方案更具靶向性和毒性更小的免疫疗法， needed.

项目成果

T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor.

• DOI: 10.3389/fimmu.2021.761448
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Jiang H;Fu D;Bidgoli A;Paczesny S
• 通讯作者: Paczesny S

T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia.

• DOI: 10.1136/jitc-2021-002509
• 发表时间: 2021-05
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Hoseini SS;Vadlamudi M;Espinosa-Cotton M;Tran H;Feng Y;Guo HF;Xu H;Cheung I;Cheung NV
• 通讯作者: Cheung NV

Combined heterozygosity of FLT3 ITD, TET2, and DNMT3A results in aggressive leukemia.

FLT3 ITD、TET2 和 DNMT3A 的组合杂合性导致侵袭性白血病。

• DOI: 10.1172/jci.insight.162016
• 发表时间: 2022-09-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Ramdas, Baskar;Reddy, Palam Lakshmi;Mali, Raghuveer Singh;Pasupuleti, Santhosh Kumar;Zhang, Ji;Kelley, Mark R.;Paczesny, Sophie;Zhang, Chi;Kapur, Reuben
• 通讯作者: Kapur, Reuben