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

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.