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• Publikační typ
• tisková chyba MeSH

Histone deacetylases (HDACs) are involved in diverse cellular regulatory mechanisms including non-canonical functions outside the chromatin environment. Several publications have demonstrated that selective HDAC inhibitors (HDACi) can influence tumor immunogenicity and the functional activity of specific immune cells. In particular, the selective inhibition of HDAC6 has been reported to decrease tumor growth in several malignancies. However, there is still no clarity about the cellular components mediating this effect. In this study, we evaluated the HDAC6i Nexturastat A as a priming agent to facilitate the transition of the tumor microenvironment from "cold" to "hot", and potentially augment immune check-point blockade therapies. This combination modality demonstrated to significantly reduce tumor growth in syngeneic melanoma tumor models. Additionally, we observed a complete neutralization of the up-regulation of PD-L1 and other immunosuppressive pathways induced by the treatment with anti-PD-1 blockade. This combination also showed profound changes in the tumor microenvironment such as enhanced infiltration of immune cells, increased central and effector T cell memory, and a significant reduction of pro-tumorigenic M2 macrophages. The evaluation of individual components of the tumor microenvironment suggested that the in vivo anti-tumor activity of HDAC6i is mediated by its effect on tumor cells and tumor-associated macrophages, and not directly over T cells. Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically "cold" tumors and subsequently improve ongoing immune check-point blockade therapies.

• MeSH
• antiflogistika terapeutické užití   MeSH
• antigeny CD274 imunologie   MeSH
• antigeny CD279 antagonisté a inhibitory   imunologie   MeSH
• histondeacetylasa 6 antagonisté a inhibitory   imunologie   MeSH
• imunologická tolerance účinky léků   MeSH
• inhibitory histondeacetylas terapeutické užití   MeSH
• makrofágy účinky léků   imunologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory farmakoterapie   imunologie   MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH