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

0510823 - BTÚ 2020 RIV GB eng J - Journal Article
Knox, T. - Sahakian, E. - Banik, D. - Hadley, M. - Palmer, E. - Noonepalle, S. - Kim, J. - Powers, J. - Gracia-Hernandez, M. - Oliveira, V. - Cheng, F. - Chen, J. - Bařinka, Cyril - Pinilla-Ibarz, J. - Lee, N. H. - Kozikowski, A. - Villagra, A.
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.
Scientific Reports. Roč. 9, APR 16 2019 (2019), č. článku 6136. ISSN 2045-2322. E-ISSN 2045-2322
Institutional support: RVO:86652036
Keywords : HISTONE DEACETYLASE 6 * LIGAND 1 EXPRESSION * INFILTRATING LYMPHOCYTES
OECD category: Biochemistry and molecular biology
Impact factor: 3.998, year: 2019
Method of publishing: Open access
https://www.nature.com/articles/s41598-019-42237-3

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.
Permanent Link: http://hdl.handle.net/11104/0301209