Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma
Dongjiang Chen, Son B. Le, Tarun E. Hutchinson, Anda-Alexandra Calinescu, Mathew Sebastian, Dan Jin, Tianyi Liu, Ashley Ghiaseddin, Maryam Rahman, David D. Tran
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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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 12

TTFields treatment correlates with immune activation via a T1IRG-based trajectory in GBM patients.

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TTFields treatment correlates with immune activation via a T1IRG-based t...
(A) An overlay of pre-TTFields (pre-TTF, green) and post-TTF (orange) UMAP plots showing post-TTF changes. The purple broken lines denote clusters with both proportional and expression changes and the blue broken lines denote some of the clusters with expression changes only. (B–D, F, and G) Combination box-and-whisker and paired dot plots showing the proportions of the indicated clusters as percentages of total PBMCs in pre-TTF and post-TTF PBMCs in all 12 patients. Analysis was performed using Wilcoxon’s test. The whiskers are the minimum and maximum values, the lower and upper box edges the 25th and 75th percentage values, respectively, and the lines within the boxes the median. (See Supplemental Figure 22). (E) A heatmap of mean expression levels of the T1IRG pathway GO:0034340 at the single-cell, cluster-agnostic level in pre-TTF and post-TTF PBMCs in all 12 patients. (See Supplemental Figure S20A). (H and J) Heatmaps of gene expression showing logFC of expression of all genes in post-TTF compared with pre-TTF pDCs (n = 9) (H) and cDCs (n = 11) (J) in patients with detectable pre- and post-TTF counts. (See Supplemental Table 5 and Supplemental Figure 21). (I and K) GSEA of the indicated GO pathways in pDCs (I) and cDCs (K) in the same pre- and post-TTFields samples in H and J, respectively. NES, normalized enrichment score.