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 10

Immunophenotyping of TTFields-induced antitumor immunity in the GL261 GBM model.

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Immunophenotyping of TTFields-induced antitumor immunity in the GL261 GB...
(See Supplemental Figure 14). (A) Combination box-and-whisker and dot plots showing immunophenotyping of C57BL/6J mice immunized with GL261-luc in various conditions in Figure 8 for total DCs and the fractions of activated DCs, early and fully activated CD4+ and CD8+ T cells in dcLNs 3 weeks after immunization (n = 8 for Scr/TTF and n = 5 for the other 3 cohorts). (B and C) Combination box-and-whisker and dot plots showing immunophenotyping for the fractions of early and fully activated CD4+ and CD8+ T cells in PBMCs of surviving Scr/TTF GL261-luc–immunized animals 2 (B) and 3 (C) weeks after rechallenge with twice the number of parental GL261 cells as compared with a new naive cohort implanted with the same cells (for 2 weeks, n = 11 for naive and n = 7 for Scr/TTF-rechallenged; for 3 weeks, n = 4 for naive and n = 5 for Scr/TTF-rechallenged). Data are represented as mean ± SEM. 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. Comparisons were performed using 1-way ANOVA for A and Student’s t test with a 2-tailed distribution for B and C. *P < 0.05; **P < 0.01.