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STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models

Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherap...

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Autores principales: Berger, Gilles, Knelson, Erik H., Jimenez-Macias, Jorge L., Nowicki, Michal O., Han, Saemi, Panagioti, Eleni, Lizotte, Patrick H., Adu-Berchie, Kwasi, Stafford, Alexander, Dimitrakakis, Nikolaos, Zhou, Lanlan, Chiocca, E. Antonio, Mooney, David J., Barbie, David A., Lawler, Sean E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282249/
https://www.ncbi.nlm.nih.gov/pubmed/35787058
http://dx.doi.org/10.1073/pnas.2111003119
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author Berger, Gilles
Knelson, Erik H.
Jimenez-Macias, Jorge L.
Nowicki, Michal O.
Han, Saemi
Panagioti, Eleni
Lizotte, Patrick H.
Adu-Berchie, Kwasi
Stafford, Alexander
Dimitrakakis, Nikolaos
Zhou, Lanlan
Chiocca, E. Antonio
Mooney, David J.
Barbie, David A.
Lawler, Sean E.
author_facet Berger, Gilles
Knelson, Erik H.
Jimenez-Macias, Jorge L.
Nowicki, Michal O.
Han, Saemi
Panagioti, Eleni
Lizotte, Patrick H.
Adu-Berchie, Kwasi
Stafford, Alexander
Dimitrakakis, Nikolaos
Zhou, Lanlan
Chiocca, E. Antonio
Mooney, David J.
Barbie, David A.
Lawler, Sean E.
author_sort Berger, Gilles
collection PubMed
description Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100–loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade.
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spelling pubmed-92822492023-01-05 STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models Berger, Gilles Knelson, Erik H. Jimenez-Macias, Jorge L. Nowicki, Michal O. Han, Saemi Panagioti, Eleni Lizotte, Patrick H. Adu-Berchie, Kwasi Stafford, Alexander Dimitrakakis, Nikolaos Zhou, Lanlan Chiocca, E. Antonio Mooney, David J. Barbie, David A. Lawler, Sean E. Proc Natl Acad Sci U S A Biological Sciences Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100–loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade. National Academy of Sciences 2022-07-05 2022-07-12 /pmc/articles/PMC9282249/ /pubmed/35787058 http://dx.doi.org/10.1073/pnas.2111003119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Berger, Gilles
Knelson, Erik H.
Jimenez-Macias, Jorge L.
Nowicki, Michal O.
Han, Saemi
Panagioti, Eleni
Lizotte, Patrick H.
Adu-Berchie, Kwasi
Stafford, Alexander
Dimitrakakis, Nikolaos
Zhou, Lanlan
Chiocca, E. Antonio
Mooney, David J.
Barbie, David A.
Lawler, Sean E.
STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models
title STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models
title_full STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models
title_fullStr STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models
title_full_unstemmed STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models
title_short STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models
title_sort sting activation promotes robust immune response and nk cell–mediated tumor regression in glioblastoma models
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282249/
https://www.ncbi.nlm.nih.gov/pubmed/35787058
http://dx.doi.org/10.1073/pnas.2111003119
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