用转染抗原、负载 NKT 细胞配体的人细胞进行免疫接种,可通过树突状细胞引发强烈的原位免疫反应。

Vaccination with antigen-transfected, NKT cell ligand-loaded, human cells elicits robust in situ immune responses by dendritic cells.

机构信息

Research Unit for Cellular Immunotherapy, The Institute of Physical and Chemical Research (RIKEN), Research Center for Allergy and Immunology (RCAI), Yokohama, Japan.

出版信息

Cancer Res. 2013 Jan 1;73(1):62-73. doi: 10.1158/0008-5472.CAN-12-0759. Epub 2012 Oct 29.

Abstract

Both innate and adaptive immunity are crucial for cancer immunosurveillance, but precise therapeutic equations to restore immunosurveillance in patients with cancer patients have yet to be developed. In murine models, α-galactosylceramide (α-GalCer)-loaded, tumor antigen-expressing syngeneic or allogeneic cells can act as cellular adjuvants, linking the innate and adaptive immune systems. In the current study, we established human artificial adjuvant vector cells (aAVC) consisting of human HEK293 embryonic kidney cells stably transfected with the natural killer T (NKT) immune cell receptor CD1d, loaded with the CD1d ligand α-GalCer and then transfected with antigen-encoding mRNA. When administered to mice or dogs, these aAVC-activated invariant NKT (iNKT) cells elicited antigen-specific T-cell responses with no adverse events. In parallel experiments, using NOD/SCID/IL-2rγc(null)-immunodeficient (hDC-NOG) mouse model, we also showed that the human melanoma antigen, MART-1, expressed by mRNA transfected aAVCs can be cross-presented to antigen-specific T cells by human dendritic cells. Antigen-specific T-cell responses elicited and expanded by aAVCs were verified as functional in tumor immunity. Our results support the clinical development of aAVCs to harness innate and adaptive immunity for effective cancer immunotherapy.

摘要

先天免疫和适应性免疫对于癌症免疫监视都至关重要,但尚未开发出精确的治疗方案来恢复癌症患者的免疫监视。在小鼠模型中,负载α-半乳糖神经酰胺(α-GalCer)、表达肿瘤抗原的同种异体或同基因细胞可以作为细胞佐剂,将先天免疫和适应性免疫系统联系起来。在本研究中,我们建立了由稳定转染自然杀伤 T(NKT)免疫细胞受体 CD1d 的人胚肾 293 细胞(HEK293)组成的人人工佐剂载体细胞(aAVC),负载 CD1d 配体α-GalCer,然后转染编码抗原的 mRNA。当给予小鼠或狗时,这些 aAVC 激活的不变自然杀伤 T(iNKT)细胞会引发无不良反应的抗原特异性 T 细胞反应。在平行实验中,我们使用 NOD/SCID/IL-2rγc(null)免疫缺陷(hDC-NOG)小鼠模型,还表明由 mRNA 转染的 aAVC 表达的人黑色素瘤抗原 MART-1 可由人树突状细胞交叉呈递至抗原特异性 T 细胞。通过 aAVC 引发和扩增的抗原特异性 T 细胞被证明在肿瘤免疫中具有功能。我们的研究结果支持开发 aAVC 来利用先天免疫和适应性免疫进行有效的癌症免疫治疗。

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