Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma.
Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma.
复制标题
DOI：
10.1172/jci149258
复制
发表时间：
2022-04-15
影响因子：
15.9
通讯作者：
Tran, David D.
中科院分区：
文献类型：
--
作者：
Chen, Dongjiang;Le, Son B.;Hutchinson, Tarun E.;Calinescu, Anda-Alexandra;Sebastian, Mathew;Jin, Dan;Liu, Tianyi;Ghiaseddin, Ashley;Rahman, Maryam;Tran, David D.
肿瘤治疗场(TTFields)是一种被批准用于治疗胶质母细胞瘤(GBM)和恶性间皮瘤的疗法，它使用低强度、中频、交变电场的非侵入性应用来破坏有丝分裂纺锤体，导致染色体错误分离和细胞凋亡。新出现的证据表明，TTFields也可能引发炎症。然而，这种特性背后的机制以及是否可以在治疗上加以利用尚不清楚。在这里，我们报告了TTFields诱导核膜的局灶性破坏，导致大的微核团的胞浆释放，强烈招募和激活两个主要的DNA传感器-环状GMP-AMP合成酶(CGAS)和它们的同源cGAS/干扰素基因刺激物(STING)和AIM2/caspase 1炎性小体，产生促炎细胞因子、1型干扰素(T1IFN)和T1IFN反应基因。在同基因小鼠GBM模型中，TTFields处理的GBM细胞诱导了抗肿瘤记忆免疫，治愈率为42%~66%，且依赖于刺痛和AIM2。利用外周血单个核细胞的单细胞和批量RNA测序，我们通过基于T1干扰素的轨迹检测到TTFields后对GBM患者获得性免疫的强大激活，并确定了TTFields对T细胞激活和克隆性增殖的影响的基因小组特征。总而言之，这些研究确定了一种治疗策略，将TTFields用作GBM和潜在的其他实体肿瘤的癌症免疫疗法。
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.