Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma
Dongjiang Chen, … , Maryam Rahman, David D. Tran
Dongjiang Chen, … , Maryam Rahman, David D. Tran
Published February 24, 2022
Citation Information: J Clin Invest. 2022;132(8):e149258. https://doi.org/10.1172/JCI149258.
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Research Article Oncology

Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma

Abstract

Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors — cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) — and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

Authors

Dongjiang Chen, Son B. Le, Tarun E. Hutchinson, Anda-Alexandra Calinescu, Mathew Sebastian, Dan Jin, Tianyi Liu, Ashley Ghiaseddin, Maryam Rahman, David D. Tran

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Figure 2

TTFields activate the cGAS/STING inflammasome in GSCs.

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TTFields activate the cGAS/STING inflammasome in GSCs. (See Supplemental...
(See Supplemental Figure 8). (A and B) The cGAS/STING inflammasome’s components IRF3 and p65 were activated following 24 hours of TTFields, as determined by immunoblotting for p-IRF3 and p-p65 in total lysate (A) and quantified by densitometry relative to total IRF3 and p65 levels and normalized to β-actin, with values for the nontreated set to 1 (B) in the 4 GSC lines. LC3A/B-I and -II were used to confirm the general TTFields effects. (C) Confocal images of IF demonstrating increased concentration and recruitment of p-IRF3 and p65 within cytosolic micronuclei clusters and protrusions after 24-hour treatment with TTFields with DAPI counterstain in the 4 GSC lines. Scale bars: 10 μm. All experiments used triplicate samples and were repeated at least 3 times. Data are represented as mean ± SEM. Analyses were performed using Student’s t test with a 2-tailed distribution. *P < 0.05, **P < 0.01, ***P < 0.001.