The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8⁺ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

生物钟是免疫的关键调节剂，这种免疫调节的昼夜节律控制在宿主防御和肿瘤免疫监视中具有重要功能。在这里，我们使用单细胞 RNA 测序方法和结直肠癌遗传模型来识别免疫景观的时钟依赖性变化，这些变化控制着免疫抑制细胞的丰度以及随后对细胞毒性 CD8 ⁺ T 细胞的抑制。在这些免疫抑制细胞类型中，表达 PD-L1 的骨髓源性抑制细胞 (MDSC) 以有节奏的方式达到丰度峰值。上皮细胞时钟的破坏会调节细胞因子的分泌，从而促进炎症加剧、中性粒细胞的募集以及随后 MDSC 的发育。我们还表明，当与免疫抑制 MDSC 的丰度同步时，一天中不同时间的抗 PD-L1 递送最为有效。总的来说，这些数据表明肿瘤免疫抑制的昼夜节律门控可以告知免疫检查点抑制剂的时机和功效。