Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Tomaszewski, WH; Waibl-Polania, J; Chakraborty, M; Perera, J; Ratiu, J; Miggelbrink, A; McDonnell, DP; Khasraw, M; Ashley, DM; Fecci, PE; Racioppi, L; Sanchez-Perez, L; Gunn, MD; Sampson, JH

Published Date

  • October 29, 2022

Published In

Volume / Issue

  • 13 / 1

Start / End Page

  • 6483 -

PubMed ID

  • 36309495

Pubmed Central ID

  • PMC9617949

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-022-34175-y


  • eng

Conference Location

  • England