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Cited by 179interferon and immune responsesGlioma Diagnosis and TreatmentCancer Immunotherapy and Biomarkers

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

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Berger, Gilles, Knelson, Erik H., Jimenez-Macias, Jorge L., Nowicki, Michal O., Han, Saemi, Panagioti, Eleni, Lizotte, Patrick H., Adu-Berchie, Kwasi +7 more·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2111003119PMC PMC9282249
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Abstract

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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  • In post-cryoablated RMS 76-9STINGwt TME compared with RMS 76-9STING-/- TME in wild-type mice, there was a significant increase in total CD4+ T cells expressing IFN-γ and GZMB, NK cells, GZMB expression in CD8+ T cells, and Foxp3+ CD4+ cells.

    “we observed a significant increase in the total CD4+ T cells expressing IFN-γ (figure 4H) and granzyme B (GZMB; figure 4J),60–65 NK cells (figure 4N), and the amount of GZMB expression in CD8+ T cells (figure 4L) in the post-cryoablated RMS 76-9STINGwt TME as compared with RMS 76-9STING-/- TME in wild-type mice, as was Foxp3+ CD4+ cells (figure 4M).”

    From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [61]

    The Results section, “STING Activation in Intracranial GBM Models Drives Innate Immune Cell Infiltration” (page unavailable), reports increased NK-cell infiltration after STING-agonist treatment. It studies glioblastoma models, not cryoablated RMS 76-9 tumors, and does not support the stated RMS comparison or the specific IFN-γ, granzyme B, and Foxp3+ CD4+ cell increases. (LLM, conf=0.83)

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Authors
Berger, G., Knelson, E. H., Jimenez-Macias, J. L., Nowicki, M. O., Han, S., Panagioti, E., Lizotte, P. H., Adu-Berchie, K., Stafford, A., Dimitrakakis, N., Zhou, L., Chiocca, E. A., Mooney, D. J., Barbie, D. A., & Lawler, S. E.
Affiliations
  • Brigham and Women's Hospital (US)
  • Dana-Farber Cancer Institute (US)
  • Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138
  • Harvard University (US)
  • Brown University (US)
Corresponding author
  • Berger, Gilles
  • Lawler, Sean E.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-07-05
Volume
119
Issue
28
Pages
e2111003119-e2111003119
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2111003119
PMC
PMC9282249
OpenAlex
W4283824461
Cited by
179
References
9
Citations by year
2026: 48 · 2025: 60 · 2024: 34 · 2023: 31 · 2022: 6
FWCI
12.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
Funders
  • Dana-Farber/Harvard Cancer Center (P30 CA 06516, 5 P30 CA06516, CA06516, NIH 5 P30 CA06516)
  • National Institutes of Health (5 P30 CA06516, CA06516, NIH 5 P30 CA06516)
  • National Cancer Institute (NIH5P30CA06516, CA06516, P30-CA06516, P30CA006516, 5-P30 CA06516)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
glioblastoma, STING pathway, ADU-S100, STING agonist, tumor microenvironment, natural killer cells, tumor regression, tumor immunosuppression, tumor vasculature, inflammatory macrophages, neutrophils, GL261, immunological memory, NK cell depletion, cancer immunotherapy
MeSH terms
STING Protein, Animals, Brain Neoplasms, Glioblastoma, Humans, Immunity, Immunotherapy, Killer Cells, Natural, Membrane Proteins, Mice, Tumor Microenvironment

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