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NKG2D Immunoligand rG7S-MICA Enhances NK Cell-mediated Immunosurveillance in Colorectal Carcinoma

免疫监视 NKG2D公司 癌症研究 MHC I级 自然杀伤细胞 免疫疗法 细胞毒性 主要组织相容性复合体 免疫学 医学 抗原 生物 免疫系统 体外 生物化学
作者
Tong Wang,Fumou Sun,Yang Wang,Jiahao Jiang,Mingzhu Pan,Minne Yuan,Martin E. Schimpf,Xiaodian Du,Kamal Hezam,Kai Song,Min Wang,Juan Zhang
出处
期刊:Journal of Immunotherapy [Ovid Technologies (Wolters Kluwer)]
卷期号:41 (3): 109-117 被引量:13
标识
DOI:10.1097/cji.0000000000000215
摘要

Colorectal carcinoma (CRC) is one of the most common malignant cancers worldwide. The poor response of CRC to chemotherapy has whipped up the interest in targeted therapy with monoclonal antibodies for its potential efficiency. However, cetuximab, as one of the first-line targeted drugs in the treatment of CRC, has drug resistance and poor prognosis in clinic. To address this, a novel bispecific protein with CRC targeting and natural killer (NK) cell triggering was used for treatment. NK cell-mediated immunosurveillance is normally activated by the activating receptor natural killer cell receptor NK group 2, member D (NKG2D), which binds its key ligand major histocompatibility complex (MHC) class I-related chain A (MICA) expressed on the tumor cells. To trigger NK cell-mediated cytotoxicity, we fused MICA portion to a single-chain antibody fragment rG7S targeting the tumor-associated antigen CD24. In vitro, flow cytometry, cytotoxicity assay, degranulation, and cytokines release assay revealed that the fusion protein rG7S-MICA could both binds to CD24 and NKG2D which enhances NK cell sensitivity and NKG2D-mediated immunosurveillance against CD24 + CRC cells. Furthermore, in a CD24 + CRC-bearing nude mice model, rG7S-MICA effectively recruits NK cell to the tumor site and increase the release of cytokines such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), and shows potential antitumor effects. In conclusion, rG7S-MICA provides a novel immunotherapeutic strategy for CRC, which could be further developed against other CD24 + malignancies.
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