Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0695.
Graduate School of Tokyo Medical and Dental University, 113-8519, Tokyo, Japan.
Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):E6836-E6844. doi: 10.1073/pnas.1803281115. Epub 2018 Jul 2.
Recent advances in cancer immunotherapy have improved patient survival. However, only a minority of patients with pulmonary metastatic disease respond to treatment with checkpoint inhibitors. As an alternate approach, we have tested the ability of systemically administered 1V270, a toll-like receptor 7 (TLR7) agonist conjugated to a phospholipid, to inhibit lung metastases in two variant murine 4T1 breast cancer models, as well as in B16 melanoma, and Lewis lung carcinoma models. In the 4T1 breast cancer models, 1V270 therapy inhibited lung metastases if given up to a week after primary tumor initiation. The treatment protocol was facilitated by the minimal toxic effects exerted by the phospholipid TLR7 agonist compared with the unconjugated agonist. 1V270 exhibited a wide therapeutic window and minimal off-target receptor binding. The 1V270 therapy inhibited colonization by tumor cells in the lungs in an NK cell dependent manner. Additional experiments revealed that single administration of 1V270 led to tumor-specific CD8 cell-dependent adaptive immune responses that suppressed late-stage metastatic tumor growth in the lungs. T cell receptor (TCR) repertoire analyses showed that 1V270 therapy induced oligoclonal T cells in the lungs and mediastinal lymph nodes. Different animals displayed commonly shared TCR clones following 1V270 therapy. Intranasal administration of 1V270 also suppressed lung metastasis and induced tumor-specific adaptive immune responses. These results indicate that systemic 1V270 therapy can induce tumor-specific cytotoxic T cell responses to pulmonary metastatic cancers and that TCR repertoire analyses can be used to monitor, and to predict, the response to therapy.
近年来癌症免疫疗法的进展提高了患者的生存率。然而，只有少数患有肺转移疾病的患者对检查点抑制剂的治疗有反应。作为一种替代方法，我们已经测试了全身性给予 1V270 的能力，1V270 是一种与磷脂偶联的 Toll 样受体 7（TLR7）激动剂，以抑制两种变体 4T1 乳腺癌模型以及 B16 黑色素瘤和 Lewis 肺癌模型中的肺转移。在 4T1 乳腺癌模型中，如果在原发性肿瘤起始后一周内给予 1V270 治疗，就可以抑制肺转移。与未缀合的激动剂相比，磷脂 TLR7 激动剂产生的最小毒性作用促进了治疗方案的实施。1V270 表现出广泛的治疗窗口和最小的脱靶受体结合。1V270 治疗以 NK 细胞依赖性方式抑制肿瘤细胞在肺部的定植。进一步的实验表明，单次给予 1V270 导致肿瘤特异性 CD8 细胞依赖性适应性免疫反应，从而抑制肺部晚期转移性肿瘤的生长。T 细胞受体（TCR）谱分析显示，1V270 治疗在肺部和纵隔淋巴结中诱导肿瘤特异性 CD8 细胞依赖性适应性免疫反应。不同的动物在接受 1V270 治疗后显示出共同的 TCR 克隆。鼻内给予 1V270 也抑制了肺转移并诱导了肿瘤特异性适应性免疫反应。这些结果表明，全身性 1V270 治疗可以诱导针对肺转移性癌症的肿瘤特异性细胞毒性 T 细胞反应，并且 TCR 谱分析可用于监测和预测治疗反应。
