Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Ann Surg Oncol. 2024 May;31(5):2983-2995. doi: 10.1245/s10434-023-14586-x. Epub 2023 Nov 25.
BACKGROUND: The expression of programmed death-ligand 1 (PD-L1) in tumor cells is a leading cause of tumor immune escape; however, the precise mechanism underlying the regulation of PD-L1 expression in gastric cancer (GC) cells remains unknown. In this study, we aimed to investigate the potential mechanism of cancer-associated fibroblasts (CAFs) regulating PD-L1 expression in GC cells. METHODS: We evaluated the immunomodulatory effects of CAFs in GC cells in vitro via the transwell co-culture system, cytometric bead array, and Western blotting. We detected the role of interleukin (IL)-8 in affecting underlying pathways in GC cells via transfecting IL-8 small-interfering RNA (siRNA), and the protection effects of CAFs on GC cells exposed to CD8 T cells via cytotoxicity assays. RESULTS: The results revealed that CAFs upregulated PD-L1 expression of GC cells. IL-8 expression was increased after KATO III or MKN45 cells co-cultured with CAF. Additionally, CAF-derived IL-8 promoted PD-L1 expression in GC cells through the P38, JNK, and NF-κB pathways. Besides, repertaxin, an IL-8 receptors (CXCR1/2) inhibitor, reduced PD-L1 expression in GC cells by blocking the P38, JNK, and NF-κB pathways. Furthermore, the expressions of p-P38, p-JNK, and p-NF-κB decreased after GC cells co-cultured with siIL-8-treated CAF. Moreover, repertaxin attenuated the protection of CAFs to cancer cells that were resistant to CD8 T-cell cytotoxicity, and improved the antibody effects of anti-PD-L1 facilitating CD8 T-cell cytotoxicity by targeting IL-8. CONCLUSION: Targeting CAF-derived IL-8 may defeat PD-L1 upregulation-mediated immune resistance in GC cells, which provides a novel approach to improve the immunotherapeutic efficacies of patients with GC.
背景：肿瘤细胞程序性死亡配体 1（PD-L1）的表达是肿瘤免疫逃逸的主要原因；然而，胃癌（GC）细胞中 PD-L1 表达调控的确切机制尚不清楚。在这项研究中，我们旨在研究癌症相关成纤维细胞（CAFs）调节 GC 细胞中 PD-L1 表达的潜在机制。
方法：我们通过 Transwell 共培养系统、细胞因子珠阵列和 Western blot 评估 CAFs 在 GC 细胞中的免疫调节作用。我们通过转染白细胞介素（IL）-8 小干扰 RNA（siRNA）检测 IL-8 影响 GC 细胞中潜在途径的作用，以及通过细胞毒性测定检测 CAFs 对暴露于 CD8 T 细胞的 GC 细胞的保护作用。
结果：结果表明，CAFs 上调了 GC 细胞的 PD-L1 表达。KATO III 或 MKN45 细胞与 CAF 共培养后，IL-8 表达增加。此外，CAF 衍生的 IL-8 通过 P38、JNK 和 NF-κB 途径促进 GC 细胞中 PD-L1 的表达。此外，IL-8 受体（CXCR1/2）抑制剂 repertaxin 通过阻断 P38、JNK 和 NF-κB 通路减少 GC 细胞中 PD-L1 的表达。此外，GC 细胞与 siIL-8 处理的 CAF 共培养后，p-P38、p-JNK 和 p-NF-κB 的表达减少。此外，repertaxin 减弱了 CAFs 对 CD8 T 细胞细胞毒性耐药的癌细胞的保护作用，并通过靶向 IL-8 改善了抗 PD-L1 抗体增强 CD8 T 细胞细胞毒性的作用。
结论：靶向 CAF 衍生的 IL-8 可能会克服 GC 细胞中 PD-L1 上调介导的免疫抵抗，为提高 GC 患者的免疫治疗效果提供了一种新方法。
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