Osteopontin-integrin interaction as a novel molecular target for antibody-mediated immunotherapy in adult T-cell leukemia.
Osteopontin-integrin interaction as a novel molecular target for antibody-mediated immunotherapy in adult T-cell leukemia.
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DOI：
10.1186/s12977-015-0225-x
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发表时间：
2015-11-24
期刊：
影响因子：
3.3
通讯作者：
Uede T
中科院分区：
文献类型：
--
作者：
Maeda N;Ohashi T;Chagan-Yasutan H;Hattori T;Takahashi Y;Harigae H;Hasegawa H;Yamada Y;Fujii M;Maenaka K;Uede T
成人t细胞白血病（ATL）是一种预后不良的CD4+ t细胞肿瘤。先前的研究表明，ATL患者分泌的基质细胞蛋白骨桥蛋白（OPN）水平与疾病严重程度之间存在很强的相关性。在此，我们研究了OPN在ATL发病机制中的作用，以及抗OPN单克隆抗体（mAb）在NOD/ shid，IL-2Rgnull （NOG）小鼠ATL免疫治疗中的可能应用。皮下接种ATL细胞系后，NOG小鼠血浆中OPN水平升高，并与接种细胞的转移及存活时间显著相关。识别SVVYGLR基序的抗opn单抗不仅能抑制肿瘤生长，还能抑制肿瘤的侵袭和转移。该单抗也减少了激活蛋白阳性成纤维细胞的成纤维细胞的数量。然后，我们将野生型（WT）或OPN敲除小鼠分离的小鼠胚胎成纤维细胞（mef）与atl来源的TL-OmI细胞共接种到NOG小鼠中。与单独注射TL-OmI细胞相比，WT MEFs共接种小鼠的存活率明显降低，MEFs中OPN的缺失明显提高了TL-OmI接种小鼠的存活率。此外，在没有OPN的情况下，肿瘤体积和转移也减少。我们发现异种移植NOG小鼠模型可以作为评估OPN在ATL发病机制中的生理作用的有用系统。通过异种移植模型，我们发现成纤维细胞来源的OPN参与肿瘤的生长和转移，并且抗OPN单克隆抗体显著抑制肿瘤的生长和转移。我们的研究结果将导致一种新的单克隆抗体介导的免疫治疗策略，针对OPN与整合素对ATL患者肿瘤的相互作用。本文的在线版本（doi:10.1186/s12977-015-0225-x）包含补充材料，可供授权用户使用。
Adult T-cell leukemia (ATL) is a CD4+ T-cell neoplasm with a poor prognosis. A previous study has shown that there is a strong correlation between the secreted matricellular protein osteopontin (OPN) level and disease severity in ATL patients. Here, we investigated the role of OPN in ATL pathogenesis and the possible application of anti-OPN monoclonal antibody (mAb) for ATL immunotherapy in NOD/Shi-scid,IL-2Rgnull (NOG) mice. Subcutaneous inoculation of ATL cell lines into NOG mice increased the plasma level of OPN, which significantly correlated with metastasis of the inoculated cells and survival time. Administration of an SVVYGLR motif-recognizing anti-OPN mAb resulted in inhibition not only of tumor growth but also of tumor invasion and metastasis. The number of fibroblast activating protein-positive fibroblasts was also reduced by this mAb. We then co-inoculated mouse embryonic fibroblasts (MEFs) isolated from wild-type (WT) or OPN knockout mice together with ATL-derived TL-OmI cells into the NOG mice. The mice co-inoculated with WT MEFs displayed a significant decrease in survival relative to those injected with TL-OmI cells alone and the absence of OPN in MEFs markedly improved the survival rate of TL-OmI-inoculated mice. In addition, tumor volume and metastasis were also reduced in the absence of OPN. We showed that the xenograft NOG mice model can be a useful system for assessment of the physiological role of OPN in ATL pathogenesis. Using this xenograft model, we found that fibroblast-derived OPN was involved in tumor growth and metastasis, and that this tumor growth and metastasis was significantly suppressed by administration of the anti-OPN mAbs. Our findings will lead to a novel mAb-mediated immunotherapeutic strategy targeting against the interaction of OPN with integrins on the tumor of ATL patients. The online version of this article (doi:10.1186/s12977-015-0225-x) contains supplementary material, which is available to authorized users.