Interplay betweenATRXandIDH1mutations governs innate immune responses in diffuse gliomas

Author:

Hariharan Seethalakshmi,Whitfield Benjamin T.,Pirozzi Christopher J.,Waitkus Matthew S.ORCID,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.

Abstract

AbstractStimulating 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.

Publisher

Cold Spring Harbor Laboratory

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