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Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma
Targeted therapy and immunotherapy have revolutionized the treatment of metastatic skin melanoma but around half of all patients develop resistance early or late during treatment. The situation is even worse for patients with metastatic uveal melanoma (UM). Here we hypothesized that the immunotherap...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245557/ https://www.ncbi.nlm.nih.gov/pubmed/34753889 http://dx.doi.org/10.1097/CMR.0000000000000791 |
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author | Sah, Vasu R. Karlsson, Joakim Jespersen, Henrik Lindberg, Mattias F. Nilsson, Lisa M. Ny, Lars Nilsson, Jonas A. |
author_facet | Sah, Vasu R. Karlsson, Joakim Jespersen, Henrik Lindberg, Mattias F. Nilsson, Lisa M. Ny, Lars Nilsson, Jonas A. |
author_sort | Sah, Vasu R. |
collection | PubMed |
description | Targeted therapy and immunotherapy have revolutionized the treatment of metastatic skin melanoma but around half of all patients develop resistance early or late during treatment. The situation is even worse for patients with metastatic uveal melanoma (UM). Here we hypothesized that the immunotherapy of therapy-resistant skin melanoma or UM can be enhanced by epigenetic inhibitors. Cultured B16F10 cells and human UM cells were treated with the histone deacetylase inhibitor (HDACi) entinostat or BETi JQ1. Entinostat-induced HLA expression and PD-L1, but JQ1 did not. A syngeneic mouse model carrying B16-F10 melanoma cells was treated with PD-1 and CTLA4 inhibitors, which was curative. Co-treatment with the bioavailable BETi iBET726 impaired the immunotherapy effect. Monotherapy of a B16-F10 mouse model with anti-PD-1 resulted in a moderate therapeutic effect that could be enhanced by entinostat. Mice carrying PD-L1 knockout B16-F10 cells were also sensitive to entinostat. This suggests HDAC inhibition and immunotherapy could work in concert. Indeed, co-cultures of UM with HLA-matched melanoma-specific tumor-infiltrating lymphocytes (TILs) resulted in higher TIL-mediated melanoma killing when entinostat was added. Further exploration of combined immunotherapy and epigenetic therapy in metastatic melanoma resistant to PD-1 inhibition is warranted. |
format | Online Article Text |
id | pubmed-9245557 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-92455572022-07-01 Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma Sah, Vasu R. Karlsson, Joakim Jespersen, Henrik Lindberg, Mattias F. Nilsson, Lisa M. Ny, Lars Nilsson, Jonas A. Melanoma Res Original Articles: Translational Research Targeted therapy and immunotherapy have revolutionized the treatment of metastatic skin melanoma but around half of all patients develop resistance early or late during treatment. The situation is even worse for patients with metastatic uveal melanoma (UM). Here we hypothesized that the immunotherapy of therapy-resistant skin melanoma or UM can be enhanced by epigenetic inhibitors. Cultured B16F10 cells and human UM cells were treated with the histone deacetylase inhibitor (HDACi) entinostat or BETi JQ1. Entinostat-induced HLA expression and PD-L1, but JQ1 did not. A syngeneic mouse model carrying B16-F10 melanoma cells was treated with PD-1 and CTLA4 inhibitors, which was curative. Co-treatment with the bioavailable BETi iBET726 impaired the immunotherapy effect. Monotherapy of a B16-F10 mouse model with anti-PD-1 resulted in a moderate therapeutic effect that could be enhanced by entinostat. Mice carrying PD-L1 knockout B16-F10 cells were also sensitive to entinostat. This suggests HDAC inhibition and immunotherapy could work in concert. Indeed, co-cultures of UM with HLA-matched melanoma-specific tumor-infiltrating lymphocytes (TILs) resulted in higher TIL-mediated melanoma killing when entinostat was added. Further exploration of combined immunotherapy and epigenetic therapy in metastatic melanoma resistant to PD-1 inhibition is warranted. Lippincott Williams & Wilkins 2021-11-10 2022-08 /pmc/articles/PMC9245557/ /pubmed/34753889 http://dx.doi.org/10.1097/CMR.0000000000000791 Text en Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles: Translational Research Sah, Vasu R. Karlsson, Joakim Jespersen, Henrik Lindberg, Mattias F. Nilsson, Lisa M. Ny, Lars Nilsson, Jonas A. Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma |
title | Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma |
title_full | Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma |
title_fullStr | Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma |
title_full_unstemmed | Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma |
title_short | Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma |
title_sort | epigenetic therapy to enhance therapeutic effects of pd-1 inhibition in therapy-resistant melanoma |
topic | Original Articles: Translational Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245557/ https://www.ncbi.nlm.nih.gov/pubmed/34753889 http://dx.doi.org/10.1097/CMR.0000000000000791 |
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