Details

Autor(en) / Beteiligte

• 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

Titel

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas

Ist Teil von

• Nature communications, 2024-01, Vol.15 (1), p.730-730, Article 730

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 IDH1 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 IDH1 dampens baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1 inhibition. IDH1 co-expression does not interfere with the ATRX deficiency-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1 reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas.