An integral membrane constitutively active heparanase enhances the tumor infiltration capability of NK cells.

IF 6.5 2区 医学 Q1 IMMUNOLOGY
Oncoimmunology Pub Date : 2025-12-01 Epub Date: 2024-12-09 DOI:10.1080/2162402X.2024.2437917
Liborio-Ramos Sofia, Quiros-Fernandez Isaac, Ilan Neta, Soboh Soaad, Farhoud Malik, Süleymanoglu Ruken, Bennek Michele, Calleja-Vara Sara, Müller Martin, Vlodavsky Israel, Angel Cid-Arregui
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引用次数: 0

Abstract

Eradication of cancer cells by the immune system requires extravasation, infiltration and progression of immune cells through the tumor extracellular matrix (ECM). These are also critical determinants for successful adoptive cell immunotherapy of solid tumors. Together with structural proteins, such as collagens and fibronectin, heparan sulfate (HS) proteoglycans are major components of the ECM. Heparanase 1 (HPSE) is the only enzyme known to have endoglycosidase activity that degrades HS. HPSE is expressed at high levels in almost all hematopoietic cells, which suggests that it plays a relevant role in immune cell migration through solid tissues. Besides, tumor cells express also HPSE as a way to facilitate tumor cell resettlement and metastasis. Therefore, an increase in HPSE in the tumor ECM would be detrimental. Here, we analyzed the effects of constitutive expression of an active, membrane-bound HPSE on the ability of human natural killer (NK) cells to infiltrate tumors and eliminate tumor cells. We demonstrate that NK cells expressing a chimeric active form of HPSE on the cell surface as an integral membrane protein, display significantly enhanced infiltration capability into spheroids of various cancer cell lines, as well as into xenograft tumors in immunodeficient mice. As a result, tumor growth was significantly suppressed without causing noticeable side effects. Altogether, our results suggest that a constitutively expressed active HSPE on the surface of immune effector cells enhances their capability to access and eliminate tumor cells. This strategy opens new possibilities for improving adoptive immune treatments using NK cells.

整体膜组成活性肝素酶增强NK细胞的肿瘤浸润能力。
免疫系统根除癌细胞需要免疫细胞通过肿瘤细胞外基质(ECM)外渗、浸润和进展。这些也是实体瘤过继细胞免疫治疗成功的关键决定因素。与结构蛋白(如胶原蛋白和纤维连接蛋白)一起,硫酸肝素(HS)蛋白聚糖是ECM的主要成分。肝素酶1 (HPSE)是已知唯一具有降解HS的内糖苷酶活性的酶。HPSE在几乎所有造血细胞中都有高水平表达,这表明它在免疫细胞通过实体组织迁移中发挥了相关作用。此外,肿瘤细胞也表达HPSE,以促进肿瘤细胞的重新安置和转移。因此,HPSE在肿瘤ECM中的升高是有害的。在这里,我们分析了活性的膜结合HPSE的组成表达对人类自然杀伤细胞(NK)浸润肿瘤和消灭肿瘤细胞的能力的影响。我们证明在细胞表面表达HPSE嵌合活性形式作为整体膜蛋白的NK细胞,在免疫缺陷小鼠中表现出对各种癌细胞系球体以及异种移植肿瘤的浸润能力显著增强。结果,肿瘤生长被明显抑制,而没有引起明显的副作用。总之,我们的研究结果表明,免疫效应细胞表面组成性表达的活性HSPE增强了它们接近和消除肿瘤细胞的能力。这一策略为使用NK细胞改善过继性免疫治疗开辟了新的可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Oncoimmunology
Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY
CiteScore
12.50
自引率
2.80%
发文量
276
审稿时长
24 weeks
期刊介绍: OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.
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