Immune Responses and Antitumor Effect through Delivering to Antigen Presenting Cells by Optimized Conjugates Consisting of CpG-DNA and Antigenic Peptide
Immune Responses and Antitumor Effect through Delivering to Antigen Presenting Cells by Optimized Conjugates Consisting of CpG-DNA and Antigenic Peptide
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DOI：
10.1021/acs.bioconjchem.0c00523
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发表时间：
2020-11-18
影响因子：
4.7
通讯作者：
Mochizuki, Shinichi
中科院分区：
文献类型：
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作者：
Irie, Hitomi;Morita, Koji;Mochizuki, Shinichi
利用抗原特异性细胞毒性T淋巴细胞(CTL)进行免疫治疗已成为肿瘤治疗中最具吸引力的策略之一。为了在体内诱导抗原特异性CTL，将CpG-DNA和抗原共同传递给相同的抗原提呈细胞(APC)是一种很有前途的策略。在本研究中，我们制备了由40聚体CpG-DNA(CpG40)和抗原肽(OVA(257-264))组成的结合物，它们具有以下显著特征：(1)在一个分子中有多个CpG基序；(2)由于多肽和CpG-DNA之间的半胱氨酸残基的二硫键而在胞浆中发生裂解；(3)结合诱导MHC I类分子上的抗原递呈。用偶联CpG40-C-OVA(257-264)在小鼠尾部免疫，可在20 ng/头的极低多肽剂量下诱导出较强的CTL活性。研究发现，这些结合物内化到腹股沟淋巴结中表达C型甘露糖受体1(MRC1)的细胞中，表明结合物中的CpG部分不仅是TLR9激活的佐剂，也是表达MRC1的APC的载体。在荷瘤小鼠模型中，与PBS、OVA(257-264)或CpG40和OVA(257-264)的混合物相比，CpG40-C-OVA(257-264)结合物免疫的小鼠肿瘤生长延迟了很长时间。因此，CpG-C肽结合物有望成为治疗癌症和传染病的多肽疫苗的新的有效平台。
Immunotherapy using antigen-specific cytotoxic T lymphocytes (CTLs) has become one of the most attractive strategies for cancer treatment. For the induction of antigen-specific CTLs in vivo, the codelivery of CpG-DNAs and antigens to the same antigen-presenting cells (APCs) is a promising strategy. In this study, we prepared conjugates consisting of 40mer of CpG-DNA (CpG40) and antigenic peptide (OVA(257-264)), which have the following distinctive features: (1) multiple CpG motifs in a molecule; (2) cleavage in the cytosol because of the disulfide bonding via cysteine residue between peptide and CpG-DNA; (3) conjugation designed to induce antigen presentation on MHC class I molecules. Immunization with the conjugate CpG40-C-OVA(257-264) at the mouse tail base induced strong CTL activity at a very low peptide dose of 20 ng/head. It was found that the conjugates were internalized into C-type mannose receptor 1 (MRC1)-expressing cells in inguinal lymph nodes, indicating that the CpG portion in the conjugate acts as not only an adjuvant for the activation of TLR9 but also a carrier to APCs expressing MRC1. In a tumor-bearing mice model, mice immunized with CpG40-C-OVA(257-264) conjugates exhibited long delays in tumor growth compared with those treated with PBS, OVA(257-264) alone, or a mixture of CpG40 and OVA(257-264). Therefore, CpG-Cpeptide conjugates could be a new and effective platform for peptide vaccine for the treatment of cancers and infectious diseases.