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Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer
  1. Chao Lin1,
  2. Hongyong He1,
  3. Hao Liu1,
  4. Ruochen Li1,
  5. Yifan Chen2,
  6. Yangyang Qi2,
  7. Qi Jiang2,
  8. Lingli Chen3,
  9. Peipei Zhang4,
  10. Heng Zhang1,
  11. He Li1,
  12. Weijuan Zhang2,
  13. Yihong Sun1,
  14. Jiejie Xu5
  1. 1Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China
  2. 2Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
  3. 3Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
  4. 4Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  5. 5Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
  1. Correspondence to Dr Weijuan Zhang, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; weijuanzhang{at}fudan.edu.cn, Dr Yihong Sun, Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; sun.yihong{at}zs-hospital.sh.cn and Dr Jiejie Xu, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; jjxufdu{at}fudan.edu.cn

Abstract

Objective Our previous studies have identified CXCL8 as the crucial chemokine responsible for gastric cancer metastasis mediated by loss of RACK1. However, the regulatory effect of CXCL8 on immune surveillance in gastric cancer remains obscure.

Design Flow cytometry analyses were performed to examine major source of CXCL8 and phenotypes of immune cells in fresh tumour tissues from 76 patients with gastric cancer. Real-time PCR was performed to analyse CXCL8 mRNA level in gastric cancer tissues. For immunohistochemical analyses, a total of 420 patients with gastric cancer undergoing curative resection were enrolled. In vitro culture of fresh tumour tissue was performed to evaluate the potential therapeutic effect of blocking CXCL8 pathway in gastric cancer.

Results Increased level of CXCL8 indicates poor clinical outcome and tumour progression in patients with gastric cancer. In gastric cancer tissues, CXCL8 is predominantly secreted by macrophages and colony stimulating factor 2 (CSF-2) facilitates macrophage-derived CXCL8 secretion. High level of CXCL8 is associated with decreased CD8+ T cells infiltration and Ki67+ CD8+ T cells proportion. Moreover, CXCL8 also inhibits CD8+ T cells function by inducing the expression of PD-L1 on macrophages. Finally, we show that a small-molecule CXCR2 inhibitor, reparixin, drives the decreased programmed death-ligand 1 (PD-L1+) macrophages and promotes antitumour immunity. Accordingly, high levels of CXCL8+ macrophages are positively correlated with poor prognosis in patients with gastric cancer.

Conclusions CXCL8 is predominantly secreted by macrophages and contributes to the immunosuppressive microenvironment by inducing PD-L1+ macrophages in gastric cancer. CXCL8 inhibitors may drive antitumour response, providing potential therapeutic effects for patients with gastric cancer.

  • gastric cancer
  • immunotherapy
  • macrophages
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Footnotes

  • CL, HH, HL and RL contributed equally.

  • Contributors CL, HH, HL and RL for acquisition of data, analysis and interpretation of data, statistical analysis and drafting of the manuscript; YC, YQ, QJ, LC, PZ, HZ and HL for technical and material support; WZ, YS and JX for study concept and design, analysis and interpretation of data, drafting of the manuscript, obtained funding and study supervision. All authors read and approved the final manuscript.

  • Funding This study was funded by grants from National Natural Science Foundation of China (31470794, 81471621, 81472227, 81501999, 81671628, 81672324, 31770851, 81871306, 81871930) and Shanghai Sailing Program (17YF1402200, 18YF1404600).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The Clinical Research Ethics Committee of Zhongshan Hospital approved the ethical use of human subjects for this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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