Cancer Research Unit, Sumitomo Pharma Co Ltd, Osaka, Japan.
BMC Immunol. 2024 Jul 25;25(1):48. doi: 10.1186/s12865-024-00643-x.
TLR7 is a key player in the antiviral immunity. TLR7 signaling activates antigen-presenting cells including DCs and macrophages. This activation results in the adaptive immunity including T cells and B cells. Therefore, TLR7 is an important molecule of the immune system. Based on these observations, TLR7 agonists considered to become a therapy weaponize the immune system against cancer. Radiation therapy (RT) is one of the standard cancer therapies and is reported to modulate the tumor immune response. In this study, we aimed to investigate the anti-tumor activity in combination of TLR7 agonist, DSP-0509, with RT and underlying mechanism.
We showed that anti-tumor activity is enhanced by combining RT with the TLR7 agonist DSP-0509 in the CT26, LM8, and 4T1 inoculated mice models. We found that once- weekly (q1w) dosing of DSP-0509 rather than biweekly (q2w) dosing is needed to achieve superior anti-tumor activities in CT26 model. Spleen cells from the mice in RT/DSP-0509 combination treatment group showed increased tumor lytic activity, inversely correlated with tumor volume, as measured by the chromium-release cytotoxicity assay. We also found the level of cytotoxic T lymphocytes (CTLs) increased in the spleens of completely cured mice. When the mice completely cured by combination therapy were re-challenged with CT26 cells, all mice rejected CT26 cells but accepted Renca cells. This rejection was not observed with CD8 depletion. Furthermore, levels of splenic effector memory CD8 T cells were increased in the combination therapy group. To explore the factors responsible for complete cure by combination therapy, we analyzed peripheral blood leukocytes (PBLs) mRNA from completely cured mice. We found that Havcr2, Cd274, Cd80, and Il6 were a predictive signature for the complete response to combination therapy. An analysis of tumor-derived mRNA showed that combination of RT and DSP-0509 strongly increased the expression of anti-tumor effector molecules including Gzmb and Il12.
These data suggest that TLR7 agonist, DSP-0509, can be a promising concomitant when used in combination with RT by upregulating CTLs activity and gene expression of effector molecules. This combination can be an expecting new radio-immunotherapeutic strategy in clinical trials.
TLR7 是抗病毒免疫的关键分子。TLR7 信号激活抗原呈递细胞，包括树突状细胞和巨噬细胞。这种激活导致适应性免疫，包括 T 细胞和 B 细胞。因此，TLR7 是免疫系统的重要分子。基于这些观察，TLR7 激动剂被认为成为一种利用免疫系统对抗癌症的治疗武器。放射治疗（RT）是癌症的标准治疗方法之一，据报道可调节肿瘤免疫反应。在这项研究中，我们旨在研究 TLR7 激动剂 DSP-0509 与 RT 联合应用的抗肿瘤活性及其潜在机制。
我们表明，在 CT26、LM8 和 4T1 接种的小鼠模型中，TLR7 激动剂 DSP-0509 与 RT 联合应用可增强抗肿瘤活性。我们发现，在 CT26 模型中，每周一次（q1w）给药 DSP-0509 而非每两周一次（q2w）给药，可获得更好的抗肿瘤活性。来自 RT/DSP-0509 联合治疗组小鼠的脾细胞显示出肿瘤溶解活性增加，与肿瘤体积呈反比，通过铬释放细胞毒性测定法测量。我们还发现，在完全治愈的小鼠脾脏中，细胞毒性 T 淋巴细胞（CTLs）水平增加。当完全治愈的小鼠通过联合治疗再次受到 CT26 细胞的挑战时，所有小鼠均排斥 CT26 细胞，但接受 Renca 细胞。这种排斥作用未观察到 CD8 耗竭。此外，在联合治疗组中，脾脏效应记忆 CD8 T 细胞的水平增加。为了探索联合治疗完全治愈的原因，我们分析了完全治愈小鼠外周血白细胞（PBLs）的 mRNA。我们发现 Havcr2、Cd274、Cd80 和 Il6 是对联合治疗完全反应的预测特征。对肿瘤衍生 mRNA 的分析表明，RT 和 DSP-0509 的联合强烈增加了包括 Gzmb 和 Il12 在内的抗肿瘤效应分子的表达。
这些数据表明，TLR7 激动剂 DSP-0509 通过上调 CTLs 活性和效应分子的基因表达，与 RT 联合使用时可能成为一种有前途的伴随治疗方法。这种联合可能成为临床试验中一种有前景的新型放射免疫治疗策略。
