Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.

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,

SUBMITTER: Tomaszewski WH 

PROVIDER: S-EPMC9617949 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature