美国加州大学欧文分校Selma Masri等研究人员合作发现，肿瘤免疫抑制的昼夜节律控制影响免疫检查点阻断剂的疗效。2024年5月28日，《自然—免疫学》杂志在线发表了这项成果。

研究人员使用单细胞RNA测序方法和结直肠癌遗传模型来确定免疫环境的时钟依赖性变化，这种变化控制着免疫抑制细胞的丰度以及由此产生的对细胞毒性CD8⁺ T细胞的抑制。在这些免疫抑制细胞类型中，表达PD-L1的髓源性抑制细胞（MDSC）的丰度峰值是有节律的。上皮细胞时钟被破坏会调节细胞因子的分泌，而细胞因子会促进炎症的加剧、中性粒细胞的招募以及MDSC的后续发展。

研究人员还发现，当与免疫抑制性MDSC的丰富程度同步时，按日给药抗PD-L1的效果最佳。总之，这些数据表明，肿瘤免疫抑制的昼夜节律可为免疫检查点抑制剂的时机和疗效提供信息。

据悉，昼夜节律钟是免疫的关键调节器，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。

附：英文原文

Title: Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade

Author: Fortin, Bridget M., Pfeiffer, Shannon M., Insua-Rodrguez, Jacob, Alshetaiwi, Hamad, Moshensky, Alexander, Song, Wei A., Mahieu, Alisa L., Chun, Sung Kook, Lewis, Amber N., Hsu, Alex, Adam, Isam, Eng, Oliver S., Pannunzio, Nicholas R., Seldin, Marcus M., Marazzi, Ivan, Marangoni, Francesco, Lawson, Devon A., Kessenbrock, Kai, Masri, Selma

Issue&Volume: 2024-05-28

Abstract: 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.

DOI: 10.1038/s41590-024-01859-0

Source: https://www.nature.com/articles/s41590-024-01859-0