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Downregulated cytotoxic CD8+ T-cell identifies with the NKG2A-soluble HLA-E axis as a predictive biomarker and potential therapeutic target in keloids

Abstract

Keloids are an abnormal fibroproliferative wound-healing disease with a poorly understood pathogenesis, making it difficult to predict and prevent this disease in clinical settings. Identifying disease-specific signatures at the molecular and cellular levels in both the blood circulation and primary lesions is urgently needed to develop novel biomarkers for risk assessment and therapeutic targets for recurrence-free treatment. There is mounting evidence of immune cell dysregulation in keloid scarring. In this study, we aimed to profile keloid scar tissues and blood cells and found that downregulation of cytotoxic CD8+ T cells is a keloid signature in the peripheral blood and keloid lesions. Single-cell RNA sequencing revealed that the NKG2A/CD94 complex was specifically upregulated, which might contribute to the significant reduction in CTLs within the scar tissue boundary. In addition, the NKG2A/CD94 complex was associated with high serum levels of soluble human leukocyte antigen-E (sHLA-E). We subsequently measured sHLA-E in our hospital-based study cohort, consisting of 104 keloid patients, 512 healthy donors, and 100 patients with an interfering disease. The sensitivity and specificity of sHLA-E were 83.69% (87/104) and 92.16% (564/612), respectively, and hypertrophic scars and other unrelated diseases exhibited minimal interference with the test results. Furthermore, intralesional therapy with triamcinolone combined with 5-fluorouracil drastically decreased the sHLA-E levels in keloid patients with better prognostic outcomes, while an incomplete reduction in the sHLA-E levels in patient serum was associated with higher recurrence. sHLA-E may effectively serve as a diagnostic marker for assessing the risk of keloid formation and a prognostic marker for the clinical outcomes of intralesional treatment.

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Acknowledgements

The authors wish to acknowledge Prof. Min Cui from Huazhong Agricultural University (China) for her insightful assistance and Prof. Moubin Lin from Yangpu Hospital, Tongji University School of Medicine (China) for providing technical assistance. We would like to acknowledge the patients for their collaboration. This study was funded by the National Natural Science Foundation of China (Nos. 81772098, 81672247, and 82002064), Shanghai Sailing Program (No. 20YF1422700) and Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (No. 20152227). The funders of the study had no role in the design or conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. We wish to thank the editors for providing editorial assistance.

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HX, BL, YW, and YZ designed the study. HX, ZZ, and JH performed experiments and collected, analyzed, and interpreted data. JH and JS collected data and contributed to data interpretation. HX, HZ, XW, and BL wrote the manuscript. HX, ZZ, JH, and JS contributed equally to this work. All authors critically revised the manuscript.

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Correspondence to Heng Xu, Bin Li or Yixin Zhang.

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Xu, H., Zhu, Z., Hu, J. et al. Downregulated cytotoxic CD8+ T-cell identifies with the NKG2A-soluble HLA-E axis as a predictive biomarker and potential therapeutic target in keloids. Cell Mol Immunol 19, 527–539 (2022). https://doi.org/10.1038/s41423-021-00834-1

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Keywords

  • Keloid
  • Biomarker
  • T cell immunology

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