Cargando…
Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors
BACKGROUND: Although immune checkpoint inhibitors (ICIs) have influenced the treatment paradigm for multiple solid tumors, increasing evidence suggests that primary and adaptive resistance may limit the long-term efficacy of ICIs. New therapeutic strategies with other drug combinations are hence war...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648046/ https://www.ncbi.nlm.nih.gov/pubmed/36352411 http://dx.doi.org/10.1186/s12916-022-02598-5 |
_version_ | 1784827497345449984 |
---|---|
author | Zhang, Pei Du, Yang Bai, Hua Wang, Zhijie Duan, Jianchun Wang, Xin Zhong, Jia Wan, Rui Xu, Jiachen He, Xiran Wang, Di Fei, Kailun Yu, Ruofei Tian, Jie Wang, Jie |
author_facet | Zhang, Pei Du, Yang Bai, Hua Wang, Zhijie Duan, Jianchun Wang, Xin Zhong, Jia Wan, Rui Xu, Jiachen He, Xiran Wang, Di Fei, Kailun Yu, Ruofei Tian, Jie Wang, Jie |
author_sort | Zhang, Pei |
collection | PubMed |
description | BACKGROUND: Although immune checkpoint inhibitors (ICIs) have influenced the treatment paradigm for multiple solid tumors, increasing evidence suggests that primary and adaptive resistance may limit the long-term efficacy of ICIs. New therapeutic strategies with other drug combinations are hence warranted to enhance the antitumor efficacy of ICIs. As a novel tumor suppressor, histone deacetylase (HDAC) inhibitor tucidinostat has been successfully confirmed to act against hematological malignancies. However, the underlying mechanisms of action for tucidinostat and whether it can manipulate the tumor microenvironment (TME) in solid tumors remain unclear. METHODS: Three murine tumor models (4T1, LLC, and CT26) were developed to define the significant role of different doses of tucidinostat in TME. The immunotherapeutic effect of tucidinostat combined with anti-programmed cell death ligand 1 antibody (aPD-L1) was demonstrated. Furthermore, the effect of tucidinostat on phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) from lung cancer patients was investigated. RESULTS: With an optimized dose, tucidinostat could alter TME and promote the migration and infiltration of CD8(+) T cells into tumors, partially by increasing the activity of C-C motif chemokine ligand 5 (CCL5) via NF-κB signaling. Moreover, tucidinostat significantly promoted M1 polarization of macrophages and increased the in vivo antitumor efficacy of aPD-L1. Tucidinostat also enhanced the expression of the costimulatory molecules on human monocytes, suggesting a novel and improved antigen-presenting function. CONCLUSIONS: A combination regimen of tucidinostat and aPD-L1 may work synergistically to reduce tumor burden in patients with cancer by enhancing the immune function and provided a promising treatment strategy to overcome ICI treatment resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02598-5. |
format | Online Article Text |
id | pubmed-9648046 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-96480462022-11-15 Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors Zhang, Pei Du, Yang Bai, Hua Wang, Zhijie Duan, Jianchun Wang, Xin Zhong, Jia Wan, Rui Xu, Jiachen He, Xiran Wang, Di Fei, Kailun Yu, Ruofei Tian, Jie Wang, Jie BMC Med Research Article BACKGROUND: Although immune checkpoint inhibitors (ICIs) have influenced the treatment paradigm for multiple solid tumors, increasing evidence suggests that primary and adaptive resistance may limit the long-term efficacy of ICIs. New therapeutic strategies with other drug combinations are hence warranted to enhance the antitumor efficacy of ICIs. As a novel tumor suppressor, histone deacetylase (HDAC) inhibitor tucidinostat has been successfully confirmed to act against hematological malignancies. However, the underlying mechanisms of action for tucidinostat and whether it can manipulate the tumor microenvironment (TME) in solid tumors remain unclear. METHODS: Three murine tumor models (4T1, LLC, and CT26) were developed to define the significant role of different doses of tucidinostat in TME. The immunotherapeutic effect of tucidinostat combined with anti-programmed cell death ligand 1 antibody (aPD-L1) was demonstrated. Furthermore, the effect of tucidinostat on phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) from lung cancer patients was investigated. RESULTS: With an optimized dose, tucidinostat could alter TME and promote the migration and infiltration of CD8(+) T cells into tumors, partially by increasing the activity of C-C motif chemokine ligand 5 (CCL5) via NF-κB signaling. Moreover, tucidinostat significantly promoted M1 polarization of macrophages and increased the in vivo antitumor efficacy of aPD-L1. Tucidinostat also enhanced the expression of the costimulatory molecules on human monocytes, suggesting a novel and improved antigen-presenting function. CONCLUSIONS: A combination regimen of tucidinostat and aPD-L1 may work synergistically to reduce tumor burden in patients with cancer by enhancing the immune function and provided a promising treatment strategy to overcome ICI treatment resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02598-5. BioMed Central 2022-11-09 /pmc/articles/PMC9648046/ /pubmed/36352411 http://dx.doi.org/10.1186/s12916-022-02598-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Zhang, Pei Du, Yang Bai, Hua Wang, Zhijie Duan, Jianchun Wang, Xin Zhong, Jia Wan, Rui Xu, Jiachen He, Xiran Wang, Di Fei, Kailun Yu, Ruofei Tian, Jie Wang, Jie Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors |
title | Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors |
title_full | Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors |
title_fullStr | Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors |
title_full_unstemmed | Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors |
title_short | Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors |
title_sort | optimized dose selective hdac inhibitor tucidinostat overcomes anti-pd-l1 antibody resistance in experimental solid tumors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648046/ https://www.ncbi.nlm.nih.gov/pubmed/36352411 http://dx.doi.org/10.1186/s12916-022-02598-5 |
work_keys_str_mv | AT zhangpei optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT duyang optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT baihua optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT wangzhijie optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT duanjianchun optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT wangxin optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT zhongjia optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT wanrui optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT xujiachen optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT hexiran optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT wangdi optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT feikailun optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT yuruofei optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT tianjie optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors AT wangjie optimizeddoseselectivehdacinhibitortucidinostatovercomesantipdl1antibodyresistanceinexperimentalsolidtumors |