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Cancer-Associated Fibroblast-Derived IL-8 Upregulates PD-L1 Expression in Gastric Cancer Through the NF-κB Pathway

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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Data Availability

This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal.

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Acknowledgments

The authors thank Ms. Yasuda and Ms. Ogata for their excellent technical assistance.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Meiyue Lou MB, Masaaki Iwatsuki MD, PhD, FACS, Xiyu Wu MB, Weiliyun Zhang MB, Chihiro Matsumoto MD & Hideo Baba MD, PhD, FACS

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  1. Meiyue Lou MB
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  2. Masaaki Iwatsuki MD, PhD, FACS
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Correspondence to Masaaki Iwatsuki MD, PhD, FACS.

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Meiyue Lou, Masaaki Iwatsuki, Xiyu Wu, Weiliyun Zhang, Chihiro Matsumoto, and Hideo Baba have no conflicts of interest to declare.

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Lou, M., Iwatsuki, M., Wu, X. et al. Cancer-Associated Fibroblast-Derived IL-8 Upregulates PD-L1 Expression in Gastric Cancer Through the NF-κB Pathway. Ann Surg Oncol 31, 2983–2995 (2024). https://doi.org/10.1245/s10434-023-14586-x

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