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Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer
Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663837/ https://www.ncbi.nlm.nih.gov/pubmed/38025772 http://dx.doi.org/10.1016/j.isci.2023.108308 |
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author | Eisa, Nada H. Crowley, Vincent M. Elahi, Asif Kommalapati, Vamsi Krishna Serwetnyk, Michael A. Llbiyi, Taoufik Lu, Sumin Kainth, Kashish Jilani, Yasmeen Marasco, Daniela El Andaloussi, Abdeljabar Lee, Sukyeong Tsai, Francis T.F. Rodriguez, Paulo C. Munn, David Celis, Esteban Korkaya, Hasan Debbab, Abdessamad Blagg, Brian Chadli, Ahmed |
author_facet | Eisa, Nada H. Crowley, Vincent M. Elahi, Asif Kommalapati, Vamsi Krishna Serwetnyk, Michael A. Llbiyi, Taoufik Lu, Sumin Kainth, Kashish Jilani, Yasmeen Marasco, Daniela El Andaloussi, Abdeljabar Lee, Sukyeong Tsai, Francis T.F. Rodriguez, Paulo C. Munn, David Celis, Esteban Korkaya, Hasan Debbab, Abdessamad Blagg, Brian Chadli, Ahmed |
author_sort | Eisa, Nada H. |
collection | PubMed |
description | Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8(+) T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action. |
format | Online Article Text |
id | pubmed-10663837 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-106638372023-10-24 Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer Eisa, Nada H. Crowley, Vincent M. Elahi, Asif Kommalapati, Vamsi Krishna Serwetnyk, Michael A. Llbiyi, Taoufik Lu, Sumin Kainth, Kashish Jilani, Yasmeen Marasco, Daniela El Andaloussi, Abdeljabar Lee, Sukyeong Tsai, Francis T.F. Rodriguez, Paulo C. Munn, David Celis, Esteban Korkaya, Hasan Debbab, Abdessamad Blagg, Brian Chadli, Ahmed iScience Article Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8(+) T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action. Elsevier 2023-10-24 /pmc/articles/PMC10663837/ /pubmed/38025772 http://dx.doi.org/10.1016/j.isci.2023.108308 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Eisa, Nada H. Crowley, Vincent M. Elahi, Asif Kommalapati, Vamsi Krishna Serwetnyk, Michael A. Llbiyi, Taoufik Lu, Sumin Kainth, Kashish Jilani, Yasmeen Marasco, Daniela El Andaloussi, Abdeljabar Lee, Sukyeong Tsai, Francis T.F. Rodriguez, Paulo C. Munn, David Celis, Esteban Korkaya, Hasan Debbab, Abdessamad Blagg, Brian Chadli, Ahmed Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer |
title | Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer |
title_full | Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer |
title_fullStr | Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer |
title_full_unstemmed | Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer |
title_short | Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer |
title_sort | enniatin a inhibits the chaperone hsp90 and unleashes the immune system against triple-negative breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663837/ https://www.ncbi.nlm.nih.gov/pubmed/38025772 http://dx.doi.org/10.1016/j.isci.2023.108308 |
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