RT Journal Article
SR Electronic
T1 STING activation promotes robust immune response and tumor regression in glioblastoma models
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.28.481908
DO 10.1101/2022.02.28.481908
A1 Gilles Berger
A1 Erik H. Knelson
A1 Michal O. Nowicki
A1 Saemi Han
A1 Jorge L. Jimenez-Macias
A1 Patrick H. Lizotte
A1 Kwasi Adu-Berchie
A1 Alexander Stafford
A1 Nikolaos Dimitrakakis
A1 E. Antonio Chiocca
A1 David J. Mooney
A1 David A. Barbie
A1 Sean E. Lawler
YR 2022
UL http://biorxiv.org/content/early/2022/03/01/2022.02.28.481908.abstract
AB 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 cGAS-STING cytoplasmic double stranded DNA (dsDNA) 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 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. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, or immune checkpoint blockade.Competing Interest StatementThe authors have declared no competing interest.