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Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.

Publication ,  Journal Article
Tomaszewski, WH; Waibl-Polania, J; Chakraborty, M; Perera, J; Ratiu, J; Miggelbrink, A; McDonnell, DP; Khasraw, M; Ashley, DM; Fecci, PE ...
Published in: Nat Commun
October 29, 2022
Published version (DOI) Link to item

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.

Duke Scholars

Luigi Racioppi
Author Luigi Racioppi Medicine, Hematologic Malignancies and Cellular Therapy
Donald Patrick McDonnell
Author Donald Patrick McDonnell Pharmacology & Cancer Biology
Mustafa Khasraw
Author Mustafa Khasraw Neurosurgery
David Michael Ashley
Author David Michael Ashley Neurosurgery
Peter Edward Fecci
Author Peter Edward Fecci Neurosurgery
Michael Dee Gunn
Author Michael Dee Gunn Medicine, Cardiology
John Howard Sampson
Author John Howard Sampson Neurosurgery
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Published In

Nat Commun

DOI

10.1038/s41467-022-34175-y

EISSN

2041-1723

Publication Date

October 29, 2022

Volume

13

Issue

1

Start / End Page

6483

Location

England

Related Subject Headings

  • Tumor Microenvironment
  • Neurons
  • Immunosuppression Therapy
  • Humans
  • Glioblastoma
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • CD8-Positive T-Lymphocytes
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Tomaszewski, W. H., Waibl-Polania, J., Chakraborty, M., Perera, J., Ratiu, J., Miggelbrink, A., … Sampson, J. H. (2022). Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma. Nat Commun, 13(1), 6483. https://doi.org/10.1038/s41467-022-34175-y
Tomaszewski, William H., Jessica Waibl-Polania, Molly Chakraborty, Jonathan Perera, Jeremy Ratiu, Alexandra Miggelbrink, Donald P. McDonnell, et al. “Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.” Nat Commun 13, no. 1 (October 29, 2022): 6483. https://doi.org/10.1038/s41467-022-34175-y.
Tomaszewski WH, Waibl-Polania J, Chakraborty M, Perera J, Ratiu J, Miggelbrink A, et al. Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma. Nat Commun. 2022 Oct 29;13(1):6483.
Tomaszewski, William H., et al. “Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.” Nat Commun, vol. 13, no. 1, Oct. 2022, p. 6483. Pubmed, doi:10.1038/s41467-022-34175-y.
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. Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma. Nat Commun. 2022 Oct 29;13(1):6483.

Published In

Nat Commun

DOI

10.1038/s41467-022-34175-y

EISSN

2041-1723

Publication Date

October 29, 2022

Volume

13

Issue

1

Start / End Page

6483

Location

England

Related Subject Headings

  • Tumor Microenvironment
  • Neurons
  • Immunosuppression Therapy
  • Humans
  • Glioblastoma
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • CD8-Positive T-Lymphocytes