通过cGAS/STING轴增强VNP20009-CCL2-CXCL9在骨肉瘤肺转移中的抗肿瘤免疫

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Ruixuan Liu, Qi Liu, Yuming Wang, Tianyi Liu, Zhusheng Zhang, Chong Zhao, Haipeng Tao, Elizabeth Ogando-Rivas, Paul Castillo, Weibin Zhang
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引用次数: 0

摘要

背景:骨肉瘤(OS)合并肺转移由于治疗选择有限和肿瘤微环境(TME)的免疫抑制性质,仍然具有挑战性。细菌介导的癌症治疗已成为治疗实体瘤的一种很有前景的策略,但由于免疫抑制TME,其效果有限,这限制了抗肿瘤免疫反应的强度和持久性。为了克服这些挑战,我们设计了一种新的沙门氏菌菌株VNP20009-CCL2-CXCL9 (VNP- c - c),利用鼠伤寒沙门氏菌VNP20009 (VNP)固有的致瘤性,并通过趋化因子CCL2和CXCL9将效应免疫细胞募集到TME中来改善免疫调节。方法:通过电穿孔place - ccl2 - cxcl9质粒进行VNP-C-C基因工程,并进行体外验证。体外实验采用骨肉瘤细胞系和免疫细胞(树突状细胞(dc)和巨噬细胞(Mφs)),体内实验采用免疫功能低下和免疫功能正常的骨肉瘤肺转移小鼠模型,评价其抗肿瘤效果、免疫调节能力和免疫调节机制。结果:VNP-C-C在肿瘤内有效积累,触发免疫原性细胞死亡,进而激活环GMP-AMP合成酶(cGAS)/干扰素基因刺激因子(STING)通路,从而有力促进I型干扰素分泌。趋化因子CCL2和CXCL9通过向TME招募dc、m - φs和T细胞来增强免疫应答。这种精心安排的免疫调节将肿瘤相关巨噬细胞重编程为抗肿瘤表型,诱导dc成熟,显著增加肿瘤内t细胞的浸润和激活,并促进外周血淋巴器官中系统性t细胞记忆的形成。这些作用共同抑制了OS肺转移的进展,并在小鼠模型中提供了生存益处。结论:工程菌株vpp - c - c有效地将OS肺转移性TME转化为促炎环境,从而刺激强大的先天和适应性免疫反应。这为骨肉瘤肺转移提供了一条非常有前途的治疗途径,在癌症免疫治疗中具有相当大的转化潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis.

Background: Osteosarcoma (OS) with pulmonary metastasis remains challenging due to limited treatment options and the immunosuppressive nature of the tumor microenvironment (TME). Bacteria-mediated cancer therapy has emerged as a promising strategy for solid tumors but often suffers from limited efficacy due to the immunosuppressive TME, which restricts the intensity and durability of the antitumor immune response. To overcome these challenges, we engineered a novel Salmonella strain, VNP20009-CCL2-CXCL9 (VNP-C-C), leveraging the intrinsic tumor tropism of Salmonella typhimurium VNP20009 (VNP) and improving immune modulation through the recruitment of effector immune cells into the TME by the chemokines CCL2 and CXCL9.

Methods: VNP-C-C was genetically engineered through electroporation of Plac-CCL2-CXCL9 plasmid and validated in vitro. Its antitumor efficacy, immune regulation capacity and immunomodulatory mechanisms were evaluated in vitro by using OS cell lines and immune cells (dendritic cells (DCs) and macrophages (Mφs)) and in vivo by using both immunocompromised and immunocompetent mouse models of OS lung metastasis.

Results: VNP-C-C effectively accumulated within tumors, triggering immunogenic cell death and subsequently activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, thereby robustly promoting type I interferon secretion. The chemokines CCL2 and CXCL9 amplified the immune response by recruiting DCs, Mφs, and T cells to the TME. This orchestrated immune modulation reprogrammed tumor-associated macrophages to an antitumor phenotype, induced DCs maturation, significantly increased T-cell infiltration and activation within tumors, and promoted systemic T-cell memory formation in peripheral lymphoid organs. These effects collectively inhibited OS lung metastasis progression and provided survival benefits in mouse models.

Conclusion: The engineered bacterial strain VNP-C-C effectively converts the OS lung metastatic TME into a pro-inflammatory milieu, thereby stimulating robust innate and adaptive immune responses. This offers a highly promising therapeutic avenue for OS lung metastasis with considerable translational potential in cancer immunotherapy.

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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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