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

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 () and David M. Ashley ()
Additional contact information
Seethalakshmi Hariharan: Duke University Medical Center
Benjamin T. Whitfield: University of Texas MD Anderson Cancer Center
Christopher J. Pirozzi: Duke University Medical Center
Matthew S. Waitkus: Duke University Medical Center
Michael C. Brown: Duke University Medical Center
Michelle L. Bowie: Duke University Medical Center
David M. Irvin: University of Texas MD Anderson Cancer Center
Kristen Roso: Duke University Medical Center
Rebecca Fuller: Duke University Medical Center
Janell Hostettler: Duke University Medical Center
Sharvari Dharmaiah: University of Texas MD Anderson Cancer Center
Emiley A. Gibson: Duke University Medical Center
Aaron Briley: Duke University Medical Center
Avani Mangoli: Duke University Medical Center
Casey Fraley: Duke University Medical Center
Mariah Shobande: Duke University Medical Center
Kevin Stevenson: Duke University Medical Center
Gao Zhang: Duke University Medical Center
Prit Benny Malgulwar: University of Texas MD Anderson Cancer Center
Hannah Roberts: University of Texas MD Anderson Cancer Center
Martin Roskoski: Duke University Medical Center
Ivan Spasojevic: Duke Cancer Institute, Duke University Medical Center
Stephen T. Keir: Duke University Medical Center
Yiping He: Duke University Medical Center
Maria G. Castro: University of Michigan Medical Center
Jason T. Huse: University of Texas MD Anderson Cancer Center
David M. Ashley: Duke University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44932-w

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