肿瘤细胞治疗研究
英文原题：Stimulator of Interferon Genes Agonist Synergistically Amplifies Programmed Cell Death Protein-1 Blockade and Radiation-Induced Systemic Antitumor Responses via Tumor Microenvironment Enrichment.
Stimulator of Interferon Genes Agonist Synergistically Amplifies Programmed Cell Death Protein-1 Blockade and Radiation-Induced Systemic Antitumor Responses via Tumor Microenvironment Enrichment.
STING 激动剂增强 TME 中的免疫激活和细胞募集，提高免疫治疗应答。它还放大 RT 的远隔效应，促进具有临床转化潜力的全身性抗肿瘤免疫。
免疫检查点抑制剂在实体瘤中的疗效有限，且高度依赖肿瘤微环境（TME）。放射治疗（RT）重塑TME，促进T细胞浸润。我们探索了干扰素基因刺激因子（STING）激动剂联合低剂量RT和免疫治疗的抗肿瘤效果。
肿瘤细胞系（PRM-SCLC、MC38和LL2）用STING激动剂diABZI（0.001-10 µM）处理以评估细胞毒性。结合RT定量分析肿瘤细胞中趋化因子和细胞因子的mRNA表达水平，以评估免疫激活。流式细胞术评估骨髓来源树突状细胞和巨噬细胞的成熟。使用皮下荷瘤小鼠模型（PRM-SCLC、MC38、LL2）监测肿瘤体积、体重和生存期。收集肿瘤样本进行流式细胞术、免疫荧光、免疫组化和转录组测序。双侧肿瘤模型评估远隔效应，并收集肿瘤和肿瘤引流淋巴结样本。
STING 激动剂 diABZI 在测试浓度下并未直接抑制肿瘤细胞增殖。然而，当与 RT 联合使用时，diABZI 显著上调了肿瘤细胞中的趋化因子和 IFN-β mRNA 水平，同时减轻了 RT 诱导的 TGF-β 水平升高。在体外，用 STING 激动剂 + RT 处理的骨髓来源树突状细胞和巨噬细胞显示出成熟度增加。在荷瘤小鼠中，STING 激动剂增强了 RT、化疗和免疫治疗的疗效。在低剂量 RT + αPD-1 中加入 STING 激动剂可激活肿瘤浸润的 CD45 +、CD8 +、CD4 + T 细胞、NK 细胞和树突状细胞，并促进 M1 巨噬细胞极化。转录组分析显示抗原呈递和 T 细胞活化增强。在双侧肿瘤模型中，三联疗法缩小了原发性和远端肿瘤体积，并增加了 T 细胞浸润以及肿瘤引流淋巴结中 TCF1 + PD-1 + T SL 细胞的更高存在。
PURPOSE: The effectiveness of immune checkpoint inhibitors in solid tumors is limited and heavily dependent on the tumor microenvironment (TME). Radiation therapy (RT) reshapes the TME, promoting T cell infiltration. We explored the combined antitumor effects of the stimulator of interferon genes (STING) agonist with low-dose RT and immunotherapy. METHODS AND MATERIALS: Tumor cell lines (PRM-SCLC, MC38, and LL2) were treated with the STING agonist diABZI (0.001-10 µM) to assess cytotoxicity. The mRNA expression levels of chemokines and cytokines in tumor cells were quantitatively analyzed in conjunction with RT to assess immune activation. Flow cytometry assessed bone marrow-derived dendritic cell and macrophage maturation. Subcutaneous tumor-bearing mouse models (PRM-SCLC, MC38, LL2) were used to monitor tumor volume, body weight, and survival. Tumor samples were collected for flow cytometry, immunofluorescence, immunohistochemistry, and transcriptome sequencing. Bilateral tumor models assessed the abscopal effect, with tumor and tumor-draining lymph node samples collected. RESULTS: The STING agonist diABZI did not directly inhibit tumor cell proliferation at tested concentrations. However, when combined with RT, diABZI significantly upregulated chemokines and IFN-β mRNA levels in tumor cells, while mitigating the RT-induced rise in TGF-β levels. In vitro, bone marrow-derived dendritic cells and macrophages treated with STING agonist + RT showed increased maturation. In tumor-bearing mice, the STING agonist enhanced the efficacy of RT, chemotherapy, and immunotherapy. Adding STING agonist to low-dose RT + αPD-1 activated tumor-infiltrating CD45 + , CD8 + , CD4 + T cells, natural killer cells, and dendritic cells, and promoted M1 macrophage polarization. Transcriptome analysis showed enhanced antigen presentation and T cell activation. In bilateral tumor models, triple therapy reduced both primary and distant tumor volumes, with increased T cell infiltration and a higher presence of TCF1 + PD-1 + T SL cells in tumor-draining lymph nodes. CONCLUSIONS: STING agonist boosts immune activation and cell recruitment in the TME, enhancing immunotherapy response. It also amplifies the abscopal effect of RT, promoting systemic antitumor immunity with clinical translational potential.
MEMBER ACCOUNT
登录成功会直接打开下一页。
