Department of Thoracic Surgery, West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China.
Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Nat Immunol. 2024 Apr;25(4):659-670. doi: 10.1038/s41590-024-01789-x. Epub 2024 Mar 18.
Combination therapy is a promising therapeutic strategy to enhance the efficacy of immune checkpoint blockade (ICB); however, predicting drugs for effective combination is challenging. Here we developed a general data-driven method called CM-Drug for screening compounds that can boost ICB treatment efficacy based on core and minor gene sets identified between responsive and nonresponsive samples in ICB therapy. The CM-Drug method was validated using melanoma and lung cancer mouse models, with combined therapeutic efficacy demonstrated in eight of nine predicted compounds. Among these compounds, taltirelin had the strongest synergistic effect. Mechanistic analysis and experimental verification demonstrated that taltirelin can stimulate CD8 T cells and is mediated by the induction of thyroid-stimulating hormone. This study provides an effective and general method for predicting and evaluating drugs for combination therapy and identifies candidate compounds for future ICB combination therapy.
联合治疗是一种很有前途的治疗策略，可以提高免疫检查点阻断（ICB）的疗效；然而，预测有效的联合用药是具有挑战性的。在这里，我们开发了一种通用的数据驱动方法，称为 CM-Drug，用于筛选基于 ICB 治疗中响应和非响应样本之间鉴定的核心和次要基因集的化合物，以提高 ICB 治疗的疗效。该 CM-Drug 方法在黑色素瘤和肺癌小鼠模型中得到了验证，在预测的九种化合物中有八种表现出联合治疗效果。在这些化合物中，塔尔替林具有最强的协同作用。机制分析和实验验证表明，塔尔替林可以刺激 CD8 T 细胞，这是由促甲状腺激素的诱导介导的。这项研究为预测和评估联合治疗药物提供了一种有效且通用的方法，并确定了候选化合物用于未来的 ICB 联合治疗。
