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

Author

Listed:
  • Seethalakshmi Hariharan

    (Duke University Medical Center
    Duke University Medical Center)

  • Benjamin T. Whitfield

    (University of Texas MD Anderson Cancer Center)

  • Christopher J. Pirozzi

    (Duke University Medical Center
    Duke University Medical Center)

  • Matthew S. Waitkus

    (Duke University Medical Center
    Duke University Medical Center)

  • Michael C. Brown

    (Duke University Medical Center
    Duke University Medical Center)

  • Michelle L. Bowie

    (Duke University Medical Center
    Duke University Medical Center)

  • David M. Irvin

    (University of Texas MD Anderson Cancer Center)

  • Kristen Roso

    (Duke University Medical Center
    Duke University Medical Center)

  • Rebecca Fuller

    (Duke University Medical Center
    Duke University Medical Center)

  • Janell Hostettler

    (Duke University Medical Center
    Duke University Medical Center)

  • Sharvari Dharmaiah

    (University of Texas MD Anderson Cancer Center)

  • Emiley A. Gibson

    (Duke University Medical Center
    Duke University Medical Center)

  • Aaron Briley

    (Duke University Medical Center
    Duke University Medical Center)

  • Avani Mangoli

    (Duke University Medical Center
    Duke University Medical Center)

  • Casey Fraley

    (Duke University Medical Center
    Duke University Medical Center)

  • Mariah Shobande

    (Duke University Medical Center
    Duke University Medical Center)

  • Kevin Stevenson

    (Duke University Medical Center
    Duke University Medical Center)

  • Gao Zhang

    (Duke University Medical Center
    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
    Duke University Medical Center)

  • Ivan Spasojevic

    (Duke Cancer Institute, Duke University Medical Center
    Duke University Medical Center)

  • Stephen T. Keir

    (Duke University Medical Center
    Duke University Medical Center)

  • Yiping He

    (Duke University Medical Center
    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
    Duke University Medical Center)

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.

Suggested Citation

  • 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 Hostettle, 2024. "Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44932-w
    DOI: 10.1038/s41467-024-44932-w
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