| Autor: |
Seethalakshmi Hariharan, Benjamin T. Whitfield, Christopher J. Pirozzi, Matthew S. Waitkus, Michael C. Brown, Michelle L. Bowie, David M. Irvin, Kristen Roso, Rebecca Fuller, Janell Hostettler, Sharvari Dharmaiah, Emiley A. Gibson, Aaron Briley, Avani Mangoli, Casey Fraley, Mariah Shobande, Kevin Stevenson, Gao Zhang, Prit Benny Malgulwar, Hannah Roberts, Martin Roskoski, Ivan Spasojevic, Stephen T. Keir, Yiping He, Maria G. Castro, Jason T. Huse, David M. Ashley |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
bioRxiv |
| Popis: |
Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations inATRX, defining molecular alterations inIDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss andIDHmutation on innate immunity. To explore this, we generatedATRXknockout glioma models in the presence and absence of theIDH1R132Hmutation. ATRX-deficient glioma cells were sensitive to dsRNA-based innate immune agonism and exhibited impaired lethality and increased T-cell infiltrationin vivo. However, the presence ofIDH1R132Hdampened baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132Hinhibition. IDH1R132Hco-expression did not interfere with theATRXKO-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132Hreversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytoma. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
