结直肠癌特异性 IFNβ 递呈克服了功能失调的 dsRNA 介导的 I 型干扰素信号转导，从而增加了放射治疗的远隔效应。
Colorectal cancer-specific IFNβ delivery overcomes dysfunctional dsRNA-mediated type I interferon signaling to increase the abscopal effect of radiotherapy.
机构信息
Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan
Translation Research Core, China Medical University Hospital, Taichung, Taiwan.
出版信息
J Immunother Cancer. 2024 May 15;12(5):e008515. doi: 10.1136/jitc-2023-008515.
BACKGROUND
Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING signaling and increases cancer immunogenicity and enhances the antitumor immune response to increase therapeutic efficacy. However, cGAS/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC.
METHODS
Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFNβ1 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq.
RESULTS
Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8 immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFNβ1 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models.
CONCLUSION
Our results support that increasing cancer-intrinsic IFNβ1 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3.
背景
放疗（RT）引发的肿瘤内在 I 型干扰素（IFN-I）产生主要依赖于细胞质双链 DNA（dsDNA）介导的 cGAS/STING 信号通路，从而增加癌症的免疫原性并增强抗肿瘤免疫反应，以提高治疗效果。然而，结直肠癌（CRC）中的 cGAS/STING 缺失可能会抑制 RT 诱导的抗肿瘤免疫。因此，我们旨在评估 RT 诱导的 dsRNA 介导的抗肿瘤免疫反应在 CRC 患者中的重要性。
方法
通过细胞基础实验（共培养实验、共聚焦显微镜、药理抑制和免疫荧光染色）和体内实验评估细胞质 dsRNA 水平及其传感器。收集接受术前放化疗（neoCRT）的 CRC 患者的活检和手术组织，进行多重细胞因子检测、免疫组织化学分析和 SNP 基因分型。我们还构建了一种肿瘤特异性腺相关病毒（AAV）-IFNβ1 构建体，以评估其与 RT 联合治疗的疗效，并通过流式细胞术和 RNA-seq 分析免疫谱。
结果
我们的研究表明，RT 刺激癌细胞自主释放 dsRNA，激活 TLR3 介导的 IFN-I 特征，以促进抗肿瘤免疫反应。携带功能失调的 TLR3 变体的患者 neoCRT 治疗后血清中 IFN-I 相关细胞因子和肿瘤内 CD8 免疫细胞水平降低，无疾病生存率缩短。工程化的肿瘤靶向构建体 AAV-IFNβ1 显著改善了 RT 的反应，导致远处肿瘤的系统消除，并在 TLR3 功能缺陷的临床前模型中延长了生存时间。
结论
我们的结果支持增加肿瘤内在 IFNβ1 表达是一种免疫治疗策略，可增强局部晚期 CRC 患者中 RT 诱导的抗肿瘤免疫反应，这些患者的 TLR3 功能失调。
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