TLR刺激联合PD-1抗体增强微波消融对NSCLC疗效的临床前研究

IF 2.8 3区医学 Q2 ONCOLOGY Clinical & Translational Oncology Pub Date : 2024-12-19 DOI:10.1007/s12094-024-03820-x

Ying Yu, Fu Niu, Bo Sun, Shusen Zhang, Zhigang Cai

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引用次数: 0

摘要

目的：本研究采用C57BL/6荷瘤小鼠模型，探讨微波消融（MWA）联合免疫检查点阻断和TLR9刺激治疗非小细胞肺癌（NSCLC）的疗效。材料和方法：用MWA、程序性细胞死亡蛋白1阻断剂(PD-1) + MWA （MWA + P）、TLR9激动剂CpG ODNs和MWA （MWA + C）、PD-1阻断剂和CpG ODNs （P + C）、MWA + PD-1阻断剂和CpG ODNs （MWA + P + C）或不治疗荷瘤小鼠。生存时间采用Kaplan-Meyer法评价，生存曲线采用log-rank检验。MWA后第15天，联合治疗组10只小鼠接受LLC细胞再攻瘤，每5天计算再攻瘤体积。免疫组织化学和流式细胞术检测免疫细胞，酶联免疫吸附法（ELISA）检测IFN-γ、TNF-α和TGF-β浓度。结果：与未治疗组、MWA组、MWA + P组、M + C组、P + C组相比，MWA + P + C联合治疗可显著延长荷瘤小鼠生存期，减小肿瘤大小。联合治疗还保护大多数存活小鼠免受LLC肿瘤的再攻击。MWA + P + C可显著诱导肿瘤和脾脏的CD8 + t细胞，联合治疗可进一步降低Treg细胞。联合治疗组血浆肿瘤坏死因子-α (TNF-α)和干扰素-γ (IFN-γ)浓度均较其他治疗组显著升高，转化生长因子-β (TGF-β)浓度降低。结论：MWA联合免疫检查点阻断和TLR刺激可显著增强抗肿瘤疗效，增强特异性免疫应答，是治疗非小细胞肺癌（NSCLC）的一种有前景的方法。

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Preclinical study of TLR stimulation combined PD-1 antibody enhance the therapeutic effect of microwave ablation on NSCLC.

Purpose: The purpose of this study was to investigate the therapeutic efficacy of the combination of microwave ablation (MWA) with immune checkpoints blockade and TLR9 stimulation in the treatment of non-small cell lung cancer (NSCLC) using the C57BL/6 tumor-bearing mice model.

Materials and methods: Tumor-bearing mice were treated with MWA, programmed cell death protein1 blockade (PD-1) plus MWA (MWA + P), TLR9 agonist CpG ODNs and MWA (MWA + C), PD-1 blockade and CpG ODNs (P + C), MWA plus PD-1 blockade and CpG ODNs (MWA + P + C), or untreated. Survival time was evaluated with the Kaplan-Meyer method comparing survival curves by log-rank test. On day 15 after MWA, ten mice from the combination therapy group received tumor rechallenge with LLC cells and the volumes of rechallenge tumor were calculated every 5 days. Immune cells were identified by immunohistochemistry and flow cytometry, and the concentrations of IFN-γ、TNF-α and TGF-β were identified by enzyme-linked immunosorbent assay (ELISA).

Results: The MWA + P + C combination therapy significantly prolonged tumor-bearing mice survival and reduced tumor size compared to untreated group, MWA group, MWA + P group, M + C group, P + C group. The combination therapy also protected most surviving mice from LLC tumor rechallenge. CD8 + T-cell in tumor and spleen were remarkably induced by MWA + P + C and Treg cell further diminished by combination therapy. Both tumor necrosis factor-alpha (TNF-α) and interferon-gama (IFN-γ) concentrations in plasma were significantly elevated in the combination therapy group compared to other groups, while transforming growth factor Beta (TGF-β) was reduced.

Conclusion: MWA combined with immune checkpoints blockade and TLR stimulation could significantly enhance antitumor efficacy with augmented specific immune responses, and the combination therapy is a promising approach to treat non-small cell lung cancer (NSCLC).

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来源期刊

Clinical & Translational Oncology 医学-肿瘤学

CiteScore

6.20

自引率

2.90%

发文量

240

审稿时长

1 months

期刊介绍： Clinical and Translational Oncology is an international journal devoted to fostering interaction between experimental and clinical oncology. It covers all aspects of research on cancer, from the more basic discoveries dealing with both cell and molecular biology of tumour cells, to the most advanced clinical assays of conventional and new drugs. In addition, the journal has a strong commitment to facilitating the transfer of knowledge from the basic laboratory to the clinical practice, with the publication of educational series devoted to closing the gap between molecular and clinical oncologists. Molecular biology of tumours, identification of new targets for cancer therapy, and new technologies for research and treatment of cancer are the major themes covered by the educational series. Full research articles on a broad spectrum of subjects, including the molecular and cellular bases of disease, aetiology, pathophysiology, pathology, epidemiology, clinical features, and the diagnosis, prognosis and treatment of cancer, will be considered for publication.