Interleukin-17 promotes nitric oxide-dependent expression of PD-L1 in mesenchymal stem cells.

Interleukin-17 Mesenchymal stem/stromal cells Nitric oxide Programmed death-ligand 1 Tumor microenvironment

Journal

Cell & bioscience
ISSN: 2045-3701
Titre abrégé: Cell Biosci
Pays: England
ID NLM: 101561195

Informations de publication

Date de publication:
2020
Historique:
received: 29 12 2019
accepted: 13 05 2020
entrez: 9 6 2020
pubmed: 9 6 2020
medline: 9 6 2020
Statut: epublish

Résumé

Interleukin-17A (IL-17) is an evolutionary conserved cytokine and best known for its role in boosting immune response. However, recent clinical researches showed that abundant IL-17 in tumor microenvironment was often associated with poor prognosis and reduced cytotoxic T cell infiltration. These contradictory phenomena suggest that IL-17 may have unique target cells in tumor microenvironment which switch its biological consequences from pro-inflammatory to anti-inflammatory. Mesenchymal stem/stromal cells (MSCs) are a major component of the tumor microenvironment. Upon cytokine stimulation, MSCs can express a plenary of inhibitory molecules, playing a critical role in tumor development and progression. Therefore, we aim to investigate the role of IL-17 in MSC-mediated immunosuppression. We found IFNγ and TNFα, two major cytokines in tumor microenvironment, could induce programmed death-ligand 1 (PD-L1) expression in MSCs. Interestingly, IL-17 has a synergistic effect with IFNγ and TNFα in elevating PD-L1 expression in MSCs. The presence of IL-17 empowered MSCs with strong immunosuppression abilities and enabled MSCs to promote tumor progression in a PD-L1 dependent manner. The upregulated PD-L1 expression in MSCs was due to the accumulation of nitric oxide (NO). On one hand, NO donor could mimic the effects of IL-17 on MSCs; on the other hand, IL-17 failed to enhance PD-L1 expression in inducible nitric oxide synthase (iNOS) deficient MSCs or with iNOS inhibitor presence. Our study demonstrates that IL-17 can significantly increase the expression of PD-L1 by MSCs through iNOS induction. This IL-17-MSCs-PD-L1 axis shapes the immunosuppressive tumor microenvironment and facilitates tumor progression.

Sections du résumé

BACKGROUND BACKGROUND
Interleukin-17A (IL-17) is an evolutionary conserved cytokine and best known for its role in boosting immune response. However, recent clinical researches showed that abundant IL-17 in tumor microenvironment was often associated with poor prognosis and reduced cytotoxic T cell infiltration. These contradictory phenomena suggest that IL-17 may have unique target cells in tumor microenvironment which switch its biological consequences from pro-inflammatory to anti-inflammatory. Mesenchymal stem/stromal cells (MSCs) are a major component of the tumor microenvironment. Upon cytokine stimulation, MSCs can express a plenary of inhibitory molecules, playing a critical role in tumor development and progression. Therefore, we aim to investigate the role of IL-17 in MSC-mediated immunosuppression.
RESULTS RESULTS
We found IFNγ and TNFα, two major cytokines in tumor microenvironment, could induce programmed death-ligand 1 (PD-L1) expression in MSCs. Interestingly, IL-17 has a synergistic effect with IFNγ and TNFα in elevating PD-L1 expression in MSCs. The presence of IL-17 empowered MSCs with strong immunosuppression abilities and enabled MSCs to promote tumor progression in a PD-L1 dependent manner. The upregulated PD-L1 expression in MSCs was due to the accumulation of nitric oxide (NO). On one hand, NO donor could mimic the effects of IL-17 on MSCs; on the other hand, IL-17 failed to enhance PD-L1 expression in inducible nitric oxide synthase (iNOS) deficient MSCs or with iNOS inhibitor presence.
CONCLUSIONS CONCLUSIONS
Our study demonstrates that IL-17 can significantly increase the expression of PD-L1 by MSCs through iNOS induction. This IL-17-MSCs-PD-L1 axis shapes the immunosuppressive tumor microenvironment and facilitates tumor progression.

Identifiants

DOI: 10.1186/s13578-020-00431-1 PMID: 32509271 PMC: PMC7249370
pubmed: 32509271
doi: 10.1186/s13578-020-00431-1
pii: 431
pmc: PMC7249370
doi:

Types de publication

Journal Article

Langues

eng

Pagination

73

Informations de copyright

© The Author(s) 2020.

Déclaration de conflit d'intérêts

Competing interestsThe authors declare that they have no competing interests.

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Auteurs

Shijia Wang (S)

Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Academy of Sciences (CAS), Shanghai, 200031 China.

Guan Wang (G)

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.

Liying Zhang (L)

The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, 215123 China.

Fengying Li (F)

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.

Keli Liu (K)

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.

Ying Wang (Y)

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.

Yufang Shi (Y)

Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Academy of Sciences (CAS), Shanghai, 200031 China.
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.
The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, 215123 China.

Kai Cao (K)

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.

Classifications MeSH