Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
Digestive Endoscopy Center, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
Cancer Immunol Immunother. 2022 Dec;71(12):3057-3070. doi: 10.1007/s00262-022-03223-3. Epub 2022 May 28.
The pretherapeutic serum interleukin-8 (sIL-8) levels have been revealed to be increased in about half of patients with locally advanced gastric cancer. However, the roles of IL-8 in lymph node metastasis (LNM) and the underlying mechanisms remain unclear.
146 patients with primary gastric carcinoma were enrolled in this study. ELISA was used to measure IL-8 levels. The CD4/CD8 ratio and programmed cell death-1 (PD-1) expression of T cells in primary tumor tissues, tumor-draining lymph nodes (TDLNs) and non-draining lymph nodes (NDLNs) were assayed with flow cytometry. Protein expression of the molecules was determined with immunohistochemistry, western blotting or immunoprecipitation. The gastric cancer mouse tumor model with LNM was utilized to determine the role of IL-8 in regulation of tumor metastasis and progression.
The elevated sIL-8 levels were associated with LNM and poor prognosis in gastric cancer. Furthermore, sIL-8 was identified to be prominently produced by gastric cancer-associated fibroblasts (CAFs). Elevated IL-8 can up-regulate PD-1 expression in CD8 T cells, resulting in immunosuppression in primary tumors and TDLNs, which enhances LNM of gastric cancer. Molecularly, IL-8 increases PD-1 expression through JAK2/STAT3 signaling activation, and inhibits its ubiquitination via Fbxo38 down-regulation. In addition, the in vivo studies in mouse gastric cancer model demonstrated that IL-8 promotes LNM via PD-1 up-regulation in CD8 T cells.
The present study elucidates the pro-metastatic role of elevated IL-8 in gastric cancer, and provides novel insights to enhance immune checkpoint blockade therapy for anti-PD-1 in gastric cancer.
术前血清白细胞介素-8（sIL-8）水平升高已在约一半局部进展期胃癌患者中显现。然而，IL-8 在淋巴结转移（LNM）中的作用及其潜在机制仍不清楚。
本研究纳入了 146 例原发性胃癌患者。采用 ELISA 法测定 IL-8 水平。采用流式细胞术测定原发灶组织、肿瘤引流淋巴结（TDLNs）和非引流淋巴结（NDLNs）中 T 细胞的 CD4/CD8 比值和程序性细胞死亡蛋白 1（PD-1）表达。采用免疫组化、Western blot 或免疫沉淀法测定分子的蛋白表达。利用具有 LNM 的胃癌小鼠肿瘤模型，确定 IL-8 在调节肿瘤转移和进展中的作用。
升高的 sIL-8 水平与胃癌的 LNM 和不良预后相关。此外，sIL-8 被鉴定为主要由胃癌相关成纤维细胞（CAFs）产生。升高的 IL-8 可上调 CD8 T 细胞中的 PD-1 表达，导致原发灶和 TDLNs 中的免疫抑制，从而增强胃癌的 LNM。从分子水平上看，IL-8 通过 JAK2/STAT3 信号激活增加 PD-1 表达，并通过下调 Fbxo38 抑制其泛素化。此外，在小鼠胃癌模型中的体内研究表明，IL-8 通过 CD8 T 细胞中 PD-1 的上调促进 LNM。
本研究阐明了升高的 IL-8 在胃癌中的促转移作用，并为增强抗 PD-1 的免疫检查点阻断治疗提供了新的见解。
