Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
J Biomed Sci. 2023 Mar 23;30(1):20. doi: 10.1186/s12929-023-00912-8.
Although immune checkpoint blockade (ICB) therapy has brought survival benefits to patients with specific cancer types, most of cancer patients remain refractory to the ICB therapy, which is largely attributed to the immunosuppressive tumor microenvironment. Thereby, it is urgent to profile key molecules and signal pathways responsible for modification of tumor microenvironment.
Multiple databases of esophageal squamous cell carcinoma (ESCC) were integratively analyzed to screen candidate genes responsible for infiltration of CD8 T cells. Expression of pescadillo ribosomal biogenesis factor 1 (PES1) in clinical ESCC samples was examined by qRT-PCR, western blotting, and immunohistochemistry. The mechanisms of PES1 were investigated via RNA sequencing and mass spectrometry followed by immunoprecipitation and proximity ligation assay. The clinical and therapeutic significance of PES1 in ESCC was comprehensively investigated using ESCC cells and mouse model.
PES1 was significantly upregulated and correlated with poor prognosis in ESCC patients. PES1 knockdown decreased ESCC cell growth in vitro and in vivo and enhanced the efficacy of ICB therapy in mouse model, which was established through subcutaneous inoculation with ESCC cells. Analyses on RNA sequencing and mass spectrometry suggested that PES1 expression was negatively correlated with IL15 and ILF3 was one of the PES1-associated proteins. It has been known that ILF3 interacts with and stabilizes IL15 mRNA to increase IL15 protein level. Our data further indicated that PES1 interfered with the interaction between ILF3 and IL15 mRNA and impaired ILF3-mediated stabilization of IL15 mRNA, which eventually reduced the protein level of IL15. Interestingly, the inhibitory effect of ICB therapy boosted by PES1 knockdown dramatically antagonized by knockdown of IL15, which suppressed the tumor-infiltrated CD8 T cells in ESCC. Finally, we confirmed the relationships among PES1, IL15, and CD8 T cell infiltration in 10 locally advanced ESCC patients receiving ICB neoadjuvant therapy and demonstrated that ICB therapy would be more effective in those with low expression of PES1.
Altogether, our findings herein provided novel insights on biological function and clinical significance of PES1 and suggested that high expression of PES1 could suppress ILF3-IL15 axis-mediated immunosurveillance and promote resistance to ICB through restraining tumor-infiltrated CD8 T cells.
尽管免疫检查点阻断（ICB）疗法为特定癌症类型的患者带来了生存获益，但大多数癌症患者仍然对 ICB 疗法无反应，这主要归因于免疫抑制性肿瘤微环境。因此，迫切需要鉴定负责肿瘤微环境修饰的关键分子和信号通路。
综合分析多个食管鳞状细胞癌（ESCC）数据库，筛选负责 CD8 T 细胞浸润的候选基因。通过 qRT-PCR、western blot 和免疫组织化学检测临床 ESCC 样本中 pescadillo 核糖体生物发生因子 1（PES1）的表达。通过 RNA 测序和质谱分析结合免疫沉淀和邻近连接分析，研究 PES1 的机制。通过 ESCC 细胞和小鼠模型全面研究 PES1 在 ESCC 中的临床和治疗意义。
PES1 在 ESCC 患者中显著上调，并与不良预后相关。PES1 敲低可降低 ESCC 细胞的体外和体内生长，并增强小鼠模型中 ICB 治疗的疗效，该模型通过皮下接种 ESCC 细胞建立。RNA 测序和质谱分析表明，PES1 的表达与 IL15 呈负相关，ILF3 是 PES1 相关蛋白之一。已知 ILF3 与 IL15 mRNA 相互作用并稳定 IL15 mRNA，从而增加 IL15 蛋白水平。我们的数据还表明，PES1 干扰了 ILF3 与 IL15 mRNA 的相互作用，并损害了 ILF3 介导的 IL15 mRNA 的稳定，从而降低了 IL15 的蛋白水平。有趣的是，由 PES1 敲低增强的 ICB 治疗的抑制作用被 IL15 的敲低显著拮抗，这抑制了 ESCC 中的肿瘤浸润 CD8 T 细胞。最后，我们在 10 名接受 ICB 新辅助治疗的局部晚期 ESCC 患者中证实了 PES1、IL15 和 CD8 T 细胞浸润之间的关系，并表明 PES1 低表达的患者对 ICB 治疗的反应更为有效。
总的来说，我们的研究结果提供了 PES1 的生物学功能和临床意义的新见解，并表明 PES1 的高表达可以通过抑制肿瘤浸润 CD8 T 细胞来抑制 ILF3-IL15 轴介导的免疫监视，并促进对 ICB 的耐药性。
