Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.
Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.
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DOI：
10.1038/s41467-024-44932-w
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发表时间：
2024-01-25
影响因子：
16.6
通讯作者：
Ashley, David M.
中科院分区：
文献类型：
--
作者：
Hariharan, Seethalakshmi;Whitfield, Benjamin T.;Pirozzi, Christopher J.;Waitkus, Matthew S.;Brown, Michael C.;Bowie, Michelle L.;Irvin, David M.;Roso, Kristen;Fuller, Rebecca;Hostettler, Janell;Dharmaiah, Sharvari;Gibson, Emiley A.;Briley, Aaron;Mangoli, Avani;Fraley, Casey;Shobande, Mariah;Stevenson, Kevin;Zhang, Gao;Malgulwar, Prit Benny;Roberts, Hannah;Roskoski, Martin;Spasojevic, Ivan;Keir, Stephen T.;He, Yiping;Castro, Maria G.;Huse, Jason T.;Ashley, David M.
刺激先天免疫系统已被探索作为治疗神经胶质瘤的治疗选择。ATRX中的失活突变，定义IDH突变型星形细胞瘤中的分子改变，与功能失调的免疫信号传导有关。然而，关于ATRX损失和IDH突变对先天免疫的相互作用知之甚少。为了探索这一点，我们在IDH1R132H突变的存在和不存在下产生了ATRX缺陷的胶质瘤模型。ATRX缺陷型神经胶质瘤细胞对基于dsRNA的先天免疫激动敏感，并在体内表现出受损的致死性和增加的T细胞浸润。然而，IDH1R132H的存在以通过遗传和药理学IDH1R132H抑制恢复的方式抑制关键先天免疫基因和细胞因子的基线表达。IDH1R132H共表达不干扰ATRX缺陷介导的对dsRNA的敏感性。因此，ATRX失去了识别dsRNA的启动细胞，而IDH1R132H可逆地掩盖了这种启动。这项工作揭示了先天免疫作为星形细胞瘤的治疗弱点。ATRX失活经常发生在IDH突变型胶质瘤中，并与免疫功能障碍有关。在这里，使用神经胶质瘤的临床前模型，作者表明ATRX失活促进先天免疫信号传导，以响应基于双链RNA的先天免疫激动剂，这种作用在IDH突变型肿瘤中被掩盖，表现出治疗脆弱性。
Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression does not interfere with the ATRX deficiency-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas. ATRX inactivation occurs often in IDH-mutant gliomas and has been associated with immune dysfunction. Here, using preclinical models of glioma, the authors show that ATRX inactivation promotes innate immune signalling in response to double stranded RNA-based innate immune agonists, an effect that is masked in IDH-mutant tumours, presenting a therapeutic vulnerability.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
10.5
作者：
Amankulor NM;Kim Y;Arora S;Kargl J;Szulzewsky F;Hanke M;Margineantu DH;Rao A;Bolouri H;Delrow J;Hockenbery D;Houghton AM;Holland EC
通讯作者：
Holland EC
影响因子：
45.3
作者：
Mohile, Nimish A.;Messersmith, Hans;Blakeley, Jaishri
通讯作者：
Blakeley, Jaishri
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
15.9
作者：
Hu, Chengchen;Wang, Kimberly;Li, Yunqing
通讯作者：
Li, Yunqing