Enniatin a Inhibits the Chaperone Hsp90 and Unleashes the Immune System Against Triple-Negative Breast Cancer

Authors

Nada H Eisa
Vincent M Crowley
Asif Elahi
Vamsi Krishna Kommalapati
Michael A Serwetnyk
Taoufik Llbiyi
Sumin Lu
Kashish Kainth
Yasmeen Jilani
Daniela Marasco
Abdeljabar El Andaloussi
Sukyeong Lee
Francis T F Tsai
Paulo C Rodriguez
David Munn
Esteban Celis
Hasan Korkaya
Abdessamad Debbab
Brian Blagg
Ahmed Chadli

Publication Date

12-15-2023

Journal

iScience

DOI

10.1016/j.isci.2023.108308

PMID

38025772

PMCID

PMC10663837

PubMedCentral® Posted Date

10-24-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Microenvironment, Biological sciences, Molecular biology, Cancer

Abstract

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.

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