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 proliferation and enhance their activation in tumors. We also observed that the combination of VPA plus an anti-PD-1 antibody was more effective than either agent alone in both the EL4 and B16-F10 tumor models. These results suggest that VPA can effectively relieve the immunosuppressive tumor microenvironment by reducing tumor infiltration of M-MDSCs, resulting in tumor regression. Our findings also show that VPA in combination with an immunotherapeutic agent could be a potential new anti-cancer therapy.

HDAC inhibition potentiates anti-tumor activity of macrophages and enhances anti-PD-L1-mediated tumor suppression

“…In light of the robust generation of MDSCs in the 4T1 model, we examined the effect of low-dose TSA on MDSCs trafficking/accumulation. Consistent with the previous studies [ 27 , 28 ], the percentages of MDSCs were markedly reduced amongst the tumor-infiltrating immune cells of low-dose TSA treated tumor-bearing mice compared to the control group in the tumors (Supplementary Fig. 5a ).…”

“…MDSCs also contribute to immune tolerance in the TME and consequently affect the efficacy of immunotherapies [ 41 ]. Consistent with previous studies [ 27 , 28 ], our data demonstrate that HDACi leads to a marked decrease of MDSCs within the tumors. This could be due in part to downregulation of the expression of CCR2 on monocytic (M)-MDSCs by HDACi, leading to the reduced infiltration of M-MDSCs into tumors [ 28 ].…”

Suppressive Myeloid Cells Shape the Tumor Immune Microenvironment

“…Recent research has revealed that this safe drug attenuates CCR2‐dependent infiltration of M‐MDSCs and limits tumor progression in EL4 and B16‐F10 models. [ 121 ]…”

Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection

“…Valproic acid also relieves the immunosuppressive effects of MDSCs on CD8 + T cells and NK cells, enhancing their activation in tumors. 146 Adjuvant epigenetic therapy using low-dose DNA methyltransferase (5-azacytidine) and histone deacetylase (Entinostat) inhibitors disrupts the premetastatic niche by downregulating CCR2 and CXCR2, thereby inhibiting MDSC recruitment and promoting their differentiation into macrophage-like cells. 5 A combination of low-dose adjuvant epigenetic therapy and CCR2 antagonists synergistically enhance disease-free and overall survival outcomes.…”