Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas
-
Published:2024-01-25
Issue:1
Volume:15
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
Hariharan Seethalakshmi, Whitfield Benjamin T.ORCID, 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.ORCID, Briley Aaron, Mangoli AvaniORCID, Fraley Casey, Shobande Mariah, Stevenson Kevin, Zhang GaoORCID, Malgulwar Prit BennyORCID, Roberts Hannah, Roskoski Martin, Spasojevic IvanORCID, Keir Stephen T., He Yiping, Castro Maria G., Huse Jason T., Ashley David M.ORCID
Abstract
AbstractStimulating 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.
Funder
U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health V Foundation for Cancer Research Jewish Communal Fund Grant Brain Tumor Research Charity Grant U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences American Cancer Society Ben and Catherine Ivy Foundation Brockman Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference55 articles.
1. Ostrom, Q. T., Cioffi, G., Waite, K., Kruchko, C. & Barnholtz-Sloan, J. S. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014–2018. Neuro. Oncol. 23, iii1–iii105 (2021). 2. Cancer Genome Atlas Research, N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008). 3. Louis, D. N. et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro. Oncol. 23, 1231–1251 (2021). 4. Whitfield, B. T. & Huse, J. T. Classification of adult-type diffuse gliomas: impact of the World Health Organization 2021 update. Brain Pathol. 32, e13062 (2022). 5. Weller, M. et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat. Rev. Clin. Oncol. 18, 170–186 (2021).
|
|