Deakin University
Browse

File(s) not publicly available

Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma

journal contribution
posted on 2023-02-10, 05:07 authored by WH Tomaszewski, J Waibl-Polania, M Chakraborty, J Perera, J Ratiu, A Miggelbrink, DP McDonnell, Mustafa Khasraw, DM Ashley, PE Fecci, L Racioppi, L Sanchez-Perez, MD Gunn, JH Sampson
AbstractGlioblastoma (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.

History

Journal

Nature Communications

Volume

13

Article number

6483

Pagination

6483-

Location

England

ISSN

2041-1723

eISSN

2041-1723

Language

en

Publication classification

C1 Refereed article in a scholarly journal

Issue

1

Publisher

Springer Science and Business Media LLC