Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors.

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Yenan Zhang, Bohao He, Peng Zou, Mengdi Wu, Min Wei, Chuning Xu, Jie Dong, Jiwu Wei
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引用次数: 0

Abstract

Background: The pleiotropic roles of tumor-associated macrophages (TAMs) render them attractive targets in antitumor drug development. CD47/SIRPα (signal regulatory protein alpha) and CD24/Siglec-10 (sialic acid-binding immunoglobulin-like lectin 10) signaling pathways have been found to suppress macrophage phagocytosis of malignant cells. Systemic blockade of CD47/SIRPα has shown severe side effects. Intratumoral delivery of a CD47 inhibitor by oncolytic viruses (OVs) may circumvent this hurdle.

Methods: To identify the characteristics of recombinant adenovirus (AdV)-SIRPα/Siglec-10, we conducted CCK8 assay, quantitative PCR, western blot, competitive binding assay, in vitro cytotoxicity assay, ELISA and phagocytosis assay. We investigated the antitumor immune responses of AdV-SIRPα/Siglec-10 using flow cytometry, various tumor-bearing mouse models, humanized tumor-bearing mouse models, immune cell depletion, RNA sequencing, and in vitro T cell activation assay.

Results: Here, we developed a novel AdV encoding a fusion protein composed of the extracellular domains of murine or human SIRPα and Siglec-10 (SIRPα/Siglec-10), termed AdV-mSS or AdV-huSS. The SIRPα/Siglec-10 was effectively secreted by cells infected with AdV-mSS and functioned as a dual blocker of CD47 and CD24, thereby significantly enhancing macrophage phagocytosis. In a series of tumor models, including subcutaneous and ascitic H22 hepatocellular carcinoma (HCC), subcutaneous Hepa1-6 HCC, MC38 colorectal carcinoma, and Lewis lung carcinoma, AdV-mSS treatment markedly enhanced antitumor efficacy. Mechanistically, AdV-mSS reprogrammed TAMs toward an antitumor phenotype and enhanced the expression of major histocompatibility complex (MHC)-I/II, promoting CD8+T cell proliferation and activation. Depletion of either macrophages or CD8+T cells abrogated the antitumor efficacy of AdV-mSS. Similarly, in a humanized LM3 HCC mouse model, AdV-huSS significantly inhibited tumor growth and prolonged survival.

Conclusions: Dual SIRPα/Siglec-10 inhibitor delivered intratumorally by AdV not only reinvigorated the TAM-CD8+T cell axis but also potentially reduced the risk of off-target effects. Further investigation of AdV-huSS in patients with cancer is warranted in the near future.

溶瘤腺病毒靶向释放双特异性融合蛋白SIRPα/ siglece -10,使肿瘤相关巨噬细胞恢复活力,改善实体瘤的治疗效果。
背景:肿瘤相关巨噬细胞(tam)的多效性使其成为抗肿瘤药物开发的重要靶点。CD47/SIRPα(信号调节蛋白α)和CD24/ siglece -10(唾液酸结合免疫球蛋白样凝集素10)信号通路抑制恶性细胞的巨噬细胞吞噬。全身性阻断CD47/SIRPα已显示出严重的副作用。溶瘤病毒(OVs)在肿瘤内递送CD47抑制剂可能会绕过这一障碍。方法:对重组腺病毒(AdV)-SIRPα/ siglece -10进行CCK8、定量PCR、western blot、竞争结合、体外细胞毒、ELISA和吞噬实验鉴定。我们通过流式细胞术、各种荷瘤小鼠模型、人源化荷瘤小鼠模型、免疫细胞耗损、RNA测序和体外T细胞活化实验研究了AdV-SIRPα/ siglece -10的抗肿瘤免疫应答。结果:在这里,我们开发了一种新的AdV,编码由小鼠或人SIRPα和Siglec-10的细胞外结构域组成的融合蛋白(SIRPα/Siglec-10),称为AdV- mss或AdV- huss。sipr α/ siglece -10在感染AdV-mSS的细胞中有效分泌,作为CD47和CD24的双重阻断剂,从而显著增强巨噬细胞的吞噬作用。在一系列肿瘤模型中,包括皮下和腹水H22肝细胞癌(HCC)、皮下Hepa1-6肝细胞癌、MC38结直肠癌和Lewis肺癌,AdV-mSS治疗显著增强了抗肿瘤疗效。在机制上,AdV-mSS将tam重编程为抗肿瘤表型,并增强主要组织相容性复合体(MHC)-I/II的表达,促进CD8+T细胞的增殖和活化。无论是巨噬细胞还是CD8+T细胞,AdV-mSS的抗肿瘤作用都被破坏。同样,在人源化LM3肝癌小鼠模型中,AdV-huSS显著抑制肿瘤生长并延长生存期。结论:AdV给药的双重SIRPα/ siglece -10抑制剂不仅可以使TAM-CD8+T细胞轴重新活化,还可以降低脱靶效应的风险。在不久的将来,AdV-huSS在癌症患者中的进一步研究是有必要的。
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来源期刊
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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