Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression.
Abstract
Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that promote tumor progression by inhibiting anti-tumor immunity and may be the cause of patient resistance to immune checkpoint inhibitors (ICIs). Therefore, MDSCs are a promising target for cancer immunotherapy, especially in combination with ICIs. Previous studies have shown that the anticonvulsant drug valproic acid (VPA) has additional anti-cancer and immunoregulatory activities due to its inhibition of histone deacetylases. We have previously shown that VPA can attenuate the immunosuppressive function of differentiated MDSCs in vitro. In the present study, we utilized anti-PD-1-sensitive EL4 and anti-PD-1-resistant B16-F10 tumor-bearing mouse models and investigated the effects of VPA on MDSCs with the aim of enhancing the anti-cancer activity of an anti-PD-1 antibody. We showed that VPA could inhibit EL4 and B16-F10 tumor progression, which was dependent on the immune system. We further demonstrated that VPA down-regulated the expression of CCR2 on monocytic (M)-MDSCs, leading to the reduced infiltration of M-MDSCs into tumors. Importantly, we demonstrated that VPA could relieve the immunosuppressive action of MDSCs on CD8+ T-cell and NK cell proliferat...Continue Reading
References
Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells
Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential
Citations
Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection.
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