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Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells

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 spe...

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Autores principales: Knox, Tessa, Sahakian, Eva, Banik, Debarati, Hadley, Melissa, Palmer, Erica, Noonepalle, Satish, Kim, Jennifer, Powers, John, Gracia-Hernandez, Maria, Oliveira, Vasco, Cheng, Fengdong, Chen, Jie, Barinka, Cyril, Pinilla-Ibarz, Javier, Lee, Norman H., Kozikowski, Alan, Villagra, Alejandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467894/
https://www.ncbi.nlm.nih.gov/pubmed/30992475
http://dx.doi.org/10.1038/s41598-019-42237-3
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author Knox, Tessa
Sahakian, Eva
Banik, Debarati
Hadley, Melissa
Palmer, Erica
Noonepalle, Satish
Kim, Jennifer
Powers, John
Gracia-Hernandez, Maria
Oliveira, Vasco
Cheng, Fengdong
Chen, Jie
Barinka, Cyril
Pinilla-Ibarz, Javier
Lee, Norman H.
Kozikowski, Alan
Villagra, Alejandro
author_facet Knox, Tessa
Sahakian, Eva
Banik, Debarati
Hadley, Melissa
Palmer, Erica
Noonepalle, Satish
Kim, Jennifer
Powers, John
Gracia-Hernandez, Maria
Oliveira, Vasco
Cheng, Fengdong
Chen, Jie
Barinka, Cyril
Pinilla-Ibarz, Javier
Lee, Norman H.
Kozikowski, Alan
Villagra, Alejandro
author_sort Knox, Tessa
collection PubMed
description 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.
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spelling pubmed-64678942019-04-18 Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells Knox, Tessa Sahakian, Eva Banik, Debarati Hadley, Melissa Palmer, Erica Noonepalle, Satish Kim, Jennifer Powers, John Gracia-Hernandez, Maria Oliveira, Vasco Cheng, Fengdong Chen, Jie Barinka, Cyril Pinilla-Ibarz, Javier Lee, Norman H. Kozikowski, Alan Villagra, Alejandro Sci Rep Article 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. Nature Publishing Group UK 2019-04-16 /pmc/articles/PMC6467894/ /pubmed/30992475 http://dx.doi.org/10.1038/s41598-019-42237-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Knox, Tessa
Sahakian, Eva
Banik, Debarati
Hadley, Melissa
Palmer, Erica
Noonepalle, Satish
Kim, Jennifer
Powers, John
Gracia-Hernandez, Maria
Oliveira, Vasco
Cheng, Fengdong
Chen, Jie
Barinka, Cyril
Pinilla-Ibarz, Javier
Lee, Norman H.
Kozikowski, Alan
Villagra, Alejandro
Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
title Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
title_full Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
title_fullStr Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
title_full_unstemmed Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
title_short Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
title_sort selective hdac6 inhibitors improve anti-pd-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467894/
https://www.ncbi.nlm.nih.gov/pubmed/30992475
http://dx.doi.org/10.1038/s41598-019-42237-3
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