Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
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
_version_ 1785138488109170688
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
work_keys_str_mv AT eisanadah enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT crowleyvincentm enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT elahiasif enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT kommalapativamsikrishna enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT serwetnykmichaela enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT llbiyitaoufik enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT lusumin enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT kainthkashish enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT jilaniyasmeen enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT marascodaniela enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT elandaloussiabdeljabar enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT leesukyeong enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT tsaifrancistf enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT rodriguezpauloc enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT munndavid enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT celisesteban enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT korkayahasan enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT debbababdessamad enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT blaggbrian enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer
AT chadliahmed enniatinainhibitsthechaperonehsp90andunleashestheimmunesystemagainsttriplenegativebreastcancer