树突状细胞成熟是由带有 p53 的溶瘤腺病毒通过肿瘤衍生的外泌体诱导的,可增强全身抗肿瘤免疫力。

IF 4.6 2区 医学 Q2 IMMUNOLOGY Cancer Immunology, Immunotherapy Pub Date : 2024-11-05 DOI:10.1007/s00262-024-03849-5
Tomoko Ohtani, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kento Kumon, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara
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引用次数: 0

摘要

树突状细胞(DC)在癌症免疫中至关重要,因为它们通过呈现肿瘤抗原激活细胞毒性 T 细胞。最近,溶瘤病毒疗法被认为是一种全身性免疫刺激剂。我们之前开发了一种端粒酶特异性溶瘤腺病毒(OBP-301)和一种带有 p53 的 OBP-301 (OBP-702),证明这些病毒能强烈激活全身抗肿瘤免疫。然而,它们对直流细胞的影响仍不清楚。本研究旨在阐明 OBP-702 激活直流细胞的机制,尤其关注肿瘤衍生的外泌体。用 Ad-p53、OBP-301 或 OBP-702 处理人或鼠胰腺癌细胞系(Panc-1、MiaPaCa-2 和 PAN02)后,从其条件培养基中分离出外泌体(Exo53、Exo301 或 Exo702)。来自 Panc-1 和 MiaPaCa-2 细胞的 Exo702 能显著上调体外直流细胞中的 CD86、CD80、CD83(直流细胞成熟的标志物)和 IFN-γ。同样,在双侧 PAN02 皮下肿瘤模型中,源自 PAN02 细胞的 Exo702 上调了骨髓源性直流细胞中的 CD86 和 IFN-γ。外泌体释放抑制剂 GW4869 和靶向外泌体标记物的抗体抗 CD63 可抑制这种 DC 成熟。向 PAN02 皮下肿瘤瘤体内注射 OBP-702 能显著增加引流淋巴结中成熟 DC 和 CD8 阳性 T 细胞的存在,从而通过持久激活全身抗肿瘤免疫产生持久的抗肿瘤效果。总之,肿瘤衍生的外泌体在OBP-702治疗后的DC成熟过程中发挥了重要作用,并且对全身抗肿瘤免疫的激活至关重要,从而导致了脱灶效应。
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Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity.

Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. However, their effects on DCs remained unclear. In the present study, the aim was to elucidate the mechanisms of DC activation by OBP-702, focusing particularly on tumor-derived exosomes. Exosomes (Exo53, Exo301, or Exo702) were isolated from conditioned media of human or murine pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and PAN02) after treatment with Ad-p53, OBP-301, or OBP-702. Exo702 derived from Panc-1 and MiaPaCa-2 cells significantly upregulated CD86, CD80, CD83 (markers of DC maturation), and IFN-γ in DCs in vitro. Similarly, Exo702 derived from PAN02 cells upregulated CD86 and IFN-γ in bone marrow-derived DCs in a bilateral PAN02 subcutaneous tumor model. This DC maturation was inhibited by GW4869, an inhibitor of exosome release, and anti-CD63, an antibody targeting the exosome marker. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect.

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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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