微波消融联合α-PD-L1增强体外效应，通过IFN-γ和CXCL9参与的细胞因子网络促进CTL活化和肿瘤内归巢

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-17 DOI:10.1016/j.intimp.2025.114498

Fuqi Ma , Xiayi Miao , Yuhua Lin , Xuming Luo , Teng Chen , Zhenhua Ni , Xiongbiao Wang

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引用次数: 0

摘要

背景与目的微波消融术（MWA）在激发抗肿瘤免疫反应方面显示出良好的潜力，可能导致远处肿瘤的消退。然而，观测到的超视距效应仍然是适度的，其潜在的机制仍然不清楚。本研究旨在系统探讨α-PD-L1在增强MWA诱导的体外效应中的作用，并全面探讨其相关机制。方法采用Lewis肺癌模型，观察MWA与α-PD-L1联合治疗的体外效应。用微波处理后的肿瘤细胞碎片刺激骨髓源性树突状细胞（bmdc），观察其成熟状态。流式细胞术检测T细胞和树突状细胞的比例，同时定量检测IFN-γ和GzmB的表达水平。免疫荧光法检测CXCL9或PD-L1的表达。结果局部MWA治疗对远处肿瘤的体积没有明显的减少。然而，与α-PD-L1腹腔内联合注射时，可诱导明显的离体效应，使小鼠远端肿瘤体积减小，生存期延长。流式细胞术分析显示，肿瘤远处浸润性活化CD8+ T细胞增加，IFN-γ和GzmB表达上调。值得注意的是，CXCR3在CD8+ T细胞中的表达增加。CXCL9 mRNA和蛋白水平在远处肿瘤中升高，并伴有巨噬细胞浸润的增加。此外，肿瘤引流淋巴结（tdln）中的树突状细胞（dc）表现出增强的成熟。此外，体外实验表明，微波处理的Lewis细胞片段刺激后，BMDCs的成熟程度有所提高。结论smwa具有刺激全身免疫应答的潜力，但没有明显的体外效应。而MWA联合α-PD-L1处理能有效诱导体外效应的发生。这种现象似乎与细胞毒性T淋巴细胞（ctl）的激活、巨噬细胞的吞噬和dc的成熟有关，这是由IFN-γ和CXCL9等细胞因子网络促进的。

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Microwave ablation combined with α-PD-L1 enhances abscopal effect and promotes CTL activation and intratumoral homing by a cytokine network involving IFN-γ and CXCL9

Background and purpose

Microwave ablation (MWA) has demonstrated promising potential in instigating an anti-tumor immune response, potentially resulting in the regression of distant tumors. Nevertheless, the observed abscopal effect remains modest, and its underlying mechanism remains poorly elucidated. This study aims to systematically examine the utilization of α-PD-L1 to enhance the abscopal effect induced by MWA and to comprehensively investigate the associated mechanisms.

Methods

The Lewis lung cancer model was employed to investigate the abscopal effect of MWA and α-PD-L1 co-treatment. The maturation status of bone marrow-derived dendritic cells (BMDCs) was observed after stimulating with the fragments of tumor cells harvested by microwave treatment. Flow cytometry analysis was employed to scrutinize the ratio of T cells and dendritic cells, along with the quantification of IFN-γ and GzmB expression levels. The expression of CXCL9 or PD-L1 was detected by immunofluorescence.

Results

Local MWA treatment on one site of tumor did not yield a significant reduction in the volume of distant tumors. However, when combined with intraperitoneal α-PD-L1 injection, a notable abscopal effect was induced, resulting in decreased distant tumor volume and prolonged survival in mice. Flow cytometry analysis revealed an increase in infiltrating and activated CD8⁺ T cells in distant tumors, with up-regulation of IFN-γ and GzmB expression. Notably, the expression of CXCR3 was increased in CD8⁺ T cells. The mRNA and protein levels of CXCL9 were elevated within distant tumors, concomitant with increased infiltration of macrophages. Moreover, dendritic cells (DCs) in tumor-draining lymph nodes (TDLNs) exhibited enhanced maturation. Additionally, in vitro experiments showed enhanced maturation of BMDCs following stimulation with fragments of Lewis cells harvested via microwave treatment.

Conclusions

MWA exhibited the potential to stimulate systemic immune responses, it did not lead to a significant abscopal effect. However, the combination of MWA with α-PD-L1 treatment effectively induced the occurrence of the abscopal effect. This phenomenon appears to be linked to the activation of cytotoxic T lymphocytes (CTLs), phagocytosis by macrophages, and the maturation of DCs, facilitated by a cytokine network involving IFN-γ and CXCL9.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.