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Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma

Author

Listed:
  • William H. Tomaszewski

    (Duke University Medical Center)

  • Jessica Waibl-Polania

    (Duke University Medical Center)

  • Molly Chakraborty

    (Duke University)

  • Jonathan Perera

    (Duke University)

  • Jeremy Ratiu

    (Duke University Medical Center)

  • Alexandra Miggelbrink

    (Duke University Medical Center)

  • Donald P. McDonnell

    (Duke University Medical Center)

  • Mustafa Khasraw

    (Duke University Medical Center
    Duke University Medical Center)

  • David M. Ashley

    (Duke University Medical Center
    Duke University Medical Center)

  • Peter E. Fecci

    (Duke University Medical Center
    Duke University Medical Center
    Duke University Medical Center
    Duke University Medical Center)

  • Luigi Racioppi

    (Duke University School of Medicine
    University of Naples Federico II)

  • Luis Sanchez-Perez

    (Duke University Medical Center
    Duke University Medical Center)

  • Michael D. Gunn

    (Duke University Medical Center
    Duke University Medical Center
    Duke University Medical Center)

  • John H. Sampson

    (Duke University Medical Center
    Duke University Medical Center
    Duke University
    Duke University Medical Center)

Abstract

Glioblastoma (GBM) is notorious for its immunosuppressive tumor microenvironment (TME) and is refractory to immune checkpoint blockade (ICB). Here, we identify calmodulin-dependent kinase kinase 2 (CaMKK2) as a driver of ICB resistance. CaMKK2 is highly expressed in pro-tumor cells and is associated with worsened survival in patients with GBM. Host CaMKK2, specifically, reduces survival and promotes ICB resistance. Multimodal profiling of the TME reveals that CaMKK2 is associated with several ICB resistance-associated immune phenotypes. CaMKK2 promotes exhaustion in CD8+ T cells and reduces the expansion of effector CD4+ T cells, additionally limiting their tumor penetrance. CaMKK2 also maintains myeloid cells in a disease-associated microglia-like phenotype. Lastly, neuronal CaMKK2 is required for maintaining the ICB resistance-associated myeloid phenotype, is deleterious to survival, and promotes ICB resistance. Our findings reveal CaMKK2 as a contributor to ICB resistance and identify neurons as a driver of immunotherapeutic resistance in GBM.

Suggested Citation

  • William H. Tomaszewski & Jessica Waibl-Polania & Molly Chakraborty & Jonathan Perera & Jeremy Ratiu & Alexandra Miggelbrink & Donald P. McDonnell & Mustafa Khasraw & David M. Ashley & Peter E. Fecci &, 2022. "Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34175-y
    DOI: 10.1038/s41467-022-34175-y
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