H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.
H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.
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DOI：
10.1172/jci154229
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发表时间：
2022-11-15
影响因子：
15.9
通讯作者：
Castro, Maria G.
中科院分区：
文献类型：
--
作者：
Haase, Santiago;Banerjee, Kaushik;Mujeeb, Anzar A.;Hartlage, Carson S.;Nunez, Fernando M.;Nunez, Felipe J.;Alghamri, Mahmoud S.;Kadiyala, Padma;Carney, Stephen;Barissi, Marcus N.;Taher, Ayman W.;Brumley, Emily K.;Thompson, Sarah;Dreyer, Justin T.;Alindogan, Caitlin T.;Garcia-Fabiani, Maria B.;Comba, Andrea;Venneti, Sriram;Ravikumar, Visweswaran;Koschmann, Carl;Carcaboso, Angel M.;Vinci, Maria;Rao, Arvind;Yu, Jennifer S.;Lowenstein, Pedro R.;Castro, Maria G.
小儿高度神经胶质瘤（PHGGS）是美国儿童与癌症相关的主要原因。 V）。编码H3.3-G34R的细胞，我们证明了这种突变导致DNA修复途径的下调，这会增强对DNA损伤的敏感性和抑制DNA损伤反应（DDR）。 G34R突变pHGG的修复导致肿瘤外DNA的积累，该DNA激活了IFN基因的环状GMP-AMP合酶/刺激剂（CGAS/STING）途径，诱导了免疫刺激细胞因子的释放。 Pamiparib和细胞周期检查点CHK1/2抑制剂AZD7762），这些组合可导致大约50％的小鼠的长期存活。激动剂（Diabzl）增强了这些治疗的治疗效率，从而防止了phgg的生存，从而防止了PHGG的增长。
Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP–AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG–bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier–permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.