Antibody targeting of surface P-selectin glycoprotein ligand 1 leads to lymphoma apoptosis and tumorigenesis inhibition

IF 3.3 4区 医学 Q2 HEMATOLOGY
João L. Pereira, Francisca Ferreira, Nuno R. dos Santos
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引用次数: 0

Abstract

Lymphomas are a heterogeneous group of diseases that originate from T, B or natural killer cells. Lymphoma treatment is based on chemotherapy, radiotherapy, and monoclonal antibody (mAb) or other immunotherapies. The P-selectin glycoprotein ligand 1 (PSGL-1) is expressed at the surface of hematological malignant cells and has been shown to have a pro-oncogenic role in multiple myeloma and lymphoma. Here, we investigated the expression and therapeutic potential of PSGL-1 in T and B cell lymphomas. By flow cytometry analysis, we found that PSGL-1 was expressed in both T and B cell-derived lymphoma cell lines but generally at higher levels in T cell lymphoma cell lines. For most T and B cell-derived lymphoma cell lines, in vitro targeting with the PL1 mAb, which recognizes the PSGL-1 N-terminal extracellular region and blocks functional interactions with selectins, resulted in reduced cell viability. The PL1 mAb pro-apoptotic activity was shown to be dose-dependent, to be linked to increased ERK kinase phosphorylation, and to be dependent on the MAP kinase signaling pathway. Importantly, anti-PSGL-1 treatment of mice xenografted with the HUT-78 cutaneous T-cell lymphoma cell line resulted in decreased tumor growth, had no effect on in vivo proliferation, but increased the levels of apoptosis in tumors. Anti-PSGL-1 treatment of mice xenografted with a Burkitt lymphoma cell line that was resistant to anti-PSGL-1 treatment in vitro, had no impact on tumorigenesis. These findings show that PSGL-1 antibody targeting triggers lymphoma cell apoptosis and substantiates PSGL-1 as a potential target for lymphoma therapy.

Abstract Image

以表面 P-选择素糖蛋白配体 1 为靶点的抗体可导致淋巴瘤凋亡并抑制肿瘤发生。
淋巴瘤是一类起源于 T 细胞、B 细胞或自然杀伤细胞的异质性疾病。淋巴瘤的治疗以化疗、放疗、单克隆抗体(mAb)或其他免疫疗法为主。P 选择素糖蛋白配体 1(PSGL-1)在血液恶性细胞表面表达,已被证明在多发性骨髓瘤和淋巴瘤中具有促癌作用。在这里,我们研究了 PSGL-1 在 T 细胞和 B 细胞淋巴瘤中的表达和治疗潜力。通过流式细胞术分析,我们发现 PSGL-1 在 T 细胞和 B 细胞衍生的淋巴瘤细胞系中均有表达,但一般在 T 细胞淋巴瘤细胞系中表达水平较高。PL1 mAb 能识别 PSGL-1 N 端细胞外区域并阻断其与选择素的功能性相互作用,对于大多数 T 细胞和 B 细胞衍生的淋巴瘤细胞系来说,使用 PL1 mAb 进行体外靶向会导致细胞存活率降低。研究表明,PL1 mAb 促凋亡活性具有剂量依赖性,与 ERK 激酶磷酸化增加有关,并依赖于 MAP 激酶信号通路。重要的是,抗PSGL-1治疗异种移植了HUT-78皮肤T细胞淋巴瘤细胞系的小鼠可减少肿瘤生长,对体内增殖没有影响,但会增加肿瘤的凋亡水平。用对体外抗 PSGL-1 治疗具有抗药性的伯基特淋巴瘤细胞系对异种移植小鼠进行抗 PSGL-1 治疗,对肿瘤发生没有影响。这些研究结果表明,PSGL-1 抗体靶向可引发淋巴瘤细胞凋亡,并证实 PSGL-1 是治疗淋巴瘤的潜在靶点。
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来源期刊
Hematological Oncology
Hematological Oncology 医学-血液学
CiteScore
4.20
自引率
6.10%
发文量
147
审稿时长
>12 weeks
期刊介绍: Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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