在局部癌症免疫治疗中鉴定治疗活性转基因的临床前模型。

IF 6.5 2区 医学 Q1 IMMUNOLOGY
Oncoimmunology Pub Date : 2025-12-01 Epub Date: 2025-08-10 DOI:10.1080/2162402X.2025.2543620
Arne Menze, Dmitrij Ostroumov, Hans Heinrich Wedemeyer, Valery Volk, Friedrich Feuerhake, Florian Kühnel, Thomas Christian Wirth
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引用次数: 0

摘要

对于免疫原性较差的肿瘤,全身免疫疗法的疗效有限,免疫原性肿瘤抑制T细胞启动和肿瘤浸润。现代抗原载体包括病毒载体和信使RNA/脂质纳米颗粒(LNP)组合,由于它们能够同时表达多种转基因构建物,因此重新引起了人们对局部免疫治疗的兴趣。然而,由于缺乏在体内快速表达和评估转基因组合的临床前模型,鉴定具有治疗活性的组合受到阻碍。为了能够对免疫原性转基因进行实证测试,我们将强力霉素诱导的表达系统与流式细胞术和多重免疫组织化学成像相结合。在肝癌和结肠癌的动物模型中,我们证明了单个转基因对免疫环境的影响是有限的,并且严重依赖于所研究的肿瘤实体。与单一转基因相比,转基因组合在肿瘤微环境中诱导更复杂且仅部分可预测的改变,但显著提高了治疗效果。通过将转基因的表达与对抗原提呈细胞和T细胞的影响结合起来,我们发现IL-12、CXCL9和FLT3L的组合是最有希望的组合方法,可以在小鼠中实现完全的肿瘤缓解。综上所述,我们证明了我们的临床前模型能够识别治疗性转基因组合,以更有效地对实体肿瘤进行局部免疫治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A preclinical model for the identification of therapeutically active transgenes in local cancer immunotherapy.

The efficacy of systemic immunotherapies is limited for poorly immunogenic tumors which suppress T cell priming and tumor infiltration. Modern antigen carriers including viral vectors and messenger RNA/lipid nanoparticle (LNP) combinations have renewed the interest in local immunotherapy due to their ability to express multiple transgene constructs simultaneously. The identification of therapeutically active combinations, however, is hampered by the lack of preclinical models to rapidly express and evaluate transgenes combinations in vivo. To enable empirical testing of immunogenic transgenes, we have combined a doxycycline-inducible expression system with flow cytometry and multiplex immunohistochemistry imaging. In animal models of liver and colon cancer, we demonstrate that the impact of a single transgene on the immune milieu is limited and heavily dependent on the studied tumor entity. Compared to single transgenes, transgene combinations induced more complex and only partially predictable alterations in the tumor micromilieu but strongly enhanced therapeutic efficacy. By combining expression of transgenes with impact on antigen-presenting cells and T cells, we identified a combination of IL-12, CXCL9 and FLT3L as the most promising combinatorial approach, resulting in complete tumor remissions in mice. Taken together, we demonstrate the ability of our preclinical model to identify therapeutic transgene combinations for more efficacious locoregional immunotherapy of solid tumors.

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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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