Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression
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 com...
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doaj-d936bae6fbe7474ca9c4f86a7a9e39bd2021-09-24T14:41:23ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2020.17342681734268Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progressionZhiqi Xie0Tamami Ikegami1Yukio Ago2Naoki Okada3Masashi Tachibana4Osaka UniversityOsaka UniversityOsaka UniversityOsaka UniversityOsaka UniversityMyeloid-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.http://dx.doi.org/10.1080/2162402X.2020.1734268myeloid-derived suppressor cellvalproic acidccr2anti pd-1 antibodycombination therapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhiqi Xie Tamami Ikegami Yukio Ago Naoki Okada Masashi Tachibana |
spellingShingle |
Zhiqi Xie Tamami Ikegami Yukio Ago Naoki Okada Masashi Tachibana Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression OncoImmunology myeloid-derived suppressor cell valproic acid ccr2 anti pd-1 antibody combination therapy |
author_facet |
Zhiqi Xie Tamami Ikegami Yukio Ago Naoki Okada Masashi Tachibana |
author_sort |
Zhiqi Xie |
title |
Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression |
title_short |
Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression |
title_full |
Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression |
title_fullStr |
Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression |
title_full_unstemmed |
Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression |
title_sort |
valproic acid attenuates ccr2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2020-01-01 |
description |
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. |
topic |
myeloid-derived suppressor cell valproic acid ccr2 anti pd-1 antibody combination therapy |
url |
http://dx.doi.org/10.1080/2162402X.2020.1734268 |
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