Anti-CTLA-4 antibody-functionalized dendritic cell-derived exosomes targeting tumor-draining lymph nodes for effective induction of antitumor T-cell responses
Anti-CTLA-4 antibody-functionalized dendritic cell-derived exosomes targeting tumor-draining lymph nodes for effective induction of antitumor T-cell responses
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DOI：
10.1016/j.actbio.2020.08.008
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发表时间：
2020-10-01
影响因子：
9.7
通讯作者：
Kim, Jong Oh
中科院分区：
文献类型：
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作者：
Cao Dai Phung;Thanh Tung Pham;Kim, Jong Oh
目前癌症疫苗的治疗效果远未达到最佳，主要原因是抗原特异性T细胞诱导不足，以及肿瘤细胞可以劫持免疫抑制机制逃避免疫应答。产生针对癌细胞的特异性、稳健和长期的免疫应答以及免疫抑制因子的减弱对于有效的癌症疫苗接种至关重要。最近，工程外泌体特异性结合T细胞，然后刺激肿瘤特异性T细胞免疫反应已成为癌症疫苗接种的潜在替代策略。在这项研究中，我们结合疫苗接种和检查点阻断策略生成了一个双功能外泌体。用抗ctla -4抗体（EXO-OVA-mAb）修饰卵清蛋白（OVA）脉冲激活的树突状细胞制备的外泌体，以阻断该抑制分子并增强外泌体对T细胞的特异性。我们的研究提供了一种独特的策略，通过脂质锚定方法将抗ctla -4抗体功能化外泌体膜，以协同癌症疫苗接种和免疫检查点阻断对肿瘤的疗效。我们设计了以共刺激分子、mhc、抗原OVA肽和抗ctla -4抗体修饰的t细胞靶向外泌体（EXO-OVA-mAb），结合疫苗和检查点阻断策略。外泌体与肿瘤引流淋巴结中的T细胞结合增强，有效诱导T细胞活化，改善效应T细胞的肿瘤归巢，最终显著抑制肿瘤生长。因此，EXO-OVA-mAb极大地促进了T细胞的靶向，诱导了强烈的肿瘤特异性T细胞应答，增加了肿瘤内效应T细胞/调节性T细胞的比例，从而产生明显的肿瘤生长抑制作用。(C) 2020材料学报Elsevier Ltd.出版。版权所有。
The therapeutic efficacy of current cancer vaccines is far from optimal, mainly because of insufficient induction of antigen-specific T cells and because tumor cells can hijack immunosuppressive mechanisms to evade the immune responses. Generating specific, robust, and long-term immune responses against cancer cells and the attenuating of immunosuppressive factors are critical for effective cancer vaccination. Recently, the engineering of exosomes specifically bind to T cells, and then stimulating tumor-specific T-cell immune responses has emerged as a potential alternative strategy for cancer vaccination. In this study, we generated a bifunctional exosome combining the strategy of vaccination and checkpoint blockade. Exosomes prepared from Ovalbumin (OVA)-pulsed, activated dendritic cells were modified with anti-CTLA-4 antibody (EXO-OVA-mAb) to block this inhibitory molecule and to enhance the specificity of the exosomes toward T cells. Our study provides a unique strategy for functionalizing exosome membrane with anti-CTLA-4 antibody via lipid-anchoring method to synergize efficacy of cancer vaccination and immune checkpoint blockade against the tumor.Statement of SignificanceWe designed T-cell-targeting exosomes (EXO-OVA-mAb) decorated with costimulatory molecules, MHCs, antigenic OVA peptide, and anti-CTLA-4 antibody, combining the strategies of vaccines and checkpoint blockade. The exosomes showed enhanced binding to T cells in tumor-draining lymph nodes, effectively induced T-cell activation, and improved the tumor homing of effector T cells, ultimately significantly restraining tumor growth. Thus, EXO-OVA-mAb greatly facilitates T-cell targeting, induces a strong tumorspecific T-cell response, and increased the ratio of effector T cells/regulatory T cells within tumors, resulting in appreciable tumor growth inhibition. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.