CD47抗体武装溶瘤腺病毒促进嵌合抗原受体巨噬细胞吞噬和抗肿瘤免疫。

IF 13.5 1区 医学 Q1 HEMATOLOGY
Zhongbing Qi, Shichuan Hu, Jing Zhao, Xianglin Xu, Anliang Huang, Yu Qin, Yao Zhang, Qingzhe Yang, Jianchuan Hu, Chao Su, Ping Cheng
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引用次数: 0

摘要

背景:嵌合抗原受体(CAR)-T细胞治疗在血液系统恶性肿瘤中取得了成功,但在实体肿瘤中遇到了挑战。巨噬细胞作为一种潜在的有效治疗靶点,由于其独特的吞噬功能,导致了多种治疗策略的发展。本研究旨在通过将靶向PD-L1的CAR-巨噬细胞(CAR- ms)与CD47抗体武装的溶瘤腺病毒(oAd-CD47)结合,开发一种有效的实体肿瘤免疫治疗策略。方法:本研究采用腺病毒载体构建靶向PD-L1并表达IFN-γ的CAR-Ms。体外检测CAR-Ms的吞噬能力和表型。采用两种不同免疫原性的小鼠肿瘤模型,在体内研究CAR-Ms的抗肿瘤作用。随后,我们探讨了CAR-M和oAd-CD47的协同抗肿瘤作用及其潜在机制。结果:CAR-Ms表现出增强的吞噬能力和促炎(M1)表型。这些CAR-Ms显著降低了CT26结肠癌小鼠的肿瘤负荷并延长了总体生存期,CT26结肠癌是一种具有高免疫原性的模型。与CAR-Ms和oAd-CD47单药治疗相比,该联合治疗(C + o)在CT26和B16黑色素瘤小鼠模型以及ID8腹膜转移模型中获得了更优越的抗肿瘤疗效。值得注意的是,C + o治疗增强了肿瘤相关巨噬细胞(TAM)吞噬,减少了抑制性免疫细胞亚群的数量,从而增强了适应性抗肿瘤t细胞和新抗原特异性t细胞免疫。此外,C + o的协同抗肿瘤作用依赖于CD8+ T细胞。结论:CAR-Ms联合oAd-CD47的治疗策略为实体瘤的个体化靶向治疗提供了一种有前景的、新颖有效的治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CD47 antibody-armed oncolytic adenovirus promotes chimeric antigen receptor macrophage phagocytosis and antitumor immunity.

Background: Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic malignancies but has encountered challenges in solid tumors. Macrophages, being a potentially effective therapeutic target, have led to the development of several therapeutic strategies due to their unique phagocytic function. This study aimed to develop an effective solid tumor immunotherapy strategy by combining CAR macrophages (CAR-Ms) targeting PD-L1 with CD47 antibody-armed oncolytic adenovirus (oAd-CD47).

Methods: In this study, an adenoviral vector was employed to construct CAR-Ms that target PD-L1 and express IFN-γ. The phagocytic capacity and phenotype of CAR-Ms were tested in vitro. Two mouse tumor models with different immunogenicity were utilized to investigate the anti-tumor efficacy of CAR-Ms in vivo. Subsequently, the synergistic anti-tumor effects of CAR-M and oAd-CD47 and their underlying mechanisms were explored.

Results: CAR-Ms exhibited enhanced phagocytic capacity and proinflammatory (M1) phenotype. These CAR-Ms significantly reduced tumor burden and extended overall survival in mice bearing CT26 colon cancer, a model characterized by high immunogenicity. Compared with CAR-Ms and oAd-CD47 monotherapy, this combination therapy (C + o) achieved superior antitumor efficacy in the CT26 and B16 melanoma mouse models, as well as in the ID8 peritoneal metastasis model. Notably, C + o treatment enhanced tumor-associated macrophage (TAM) phagocytosis and reduced the population of inhibitory immune cell subsets, thereby resulting in enhanced adaptive antitumor T-cell and neoantigen-specific T-cell immunity. Additionally, the synergistic antitumor effect of C + o was dependent on CD8+ T cells.

Conclusion: The treatment strategy of CAR-Ms combined with oAd-CD47 provides a promising, novel and effective treatment method for individualized targeted therapy of solid tumors.

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来源期刊
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
期刊介绍: Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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