論文 - 詳細
| RRC ID | 77414 |
|---|---|
| 著者 | Lou M, Iwatsuki M, Wu X, Zhang W, Matsumoto C, Baba H. |
| タイトル | Cancer-Associated Fibroblast-Derived IL-8 Upregulates PD-L1 Expression in Gastric Cancer Through the NF-κB Pathway. |
| ジャーナル | Ann Surg Oncol |
| Abstract |
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. |
| 公開日 | 2023-11-25 |
| DOI | 10.1245/s10434-023-14586-x |
| PII | 10.1245/s10434-023-14586-x |
| PMID | 38006530 |
| IF | 4.061 |
| リソース情報 | |
| ヒト・動物細胞 | Kato III(RCB2088) MKN1(RCB1003) MKN7(RCB0999) MKN45(RCB1001) NUGC-4(RCB1939) |