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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #406878
Research Project: Molecular, Cellular, and Regulatory Aspects of Obesity Development

Location: Children's Nutrition Research Center

Title: Increased CaMKK2 expression is an adaptive response that maintains the fitness of tumor-infiltrating natural killer cells

Author
item JURAS, PATRICK - Duke University School Of Medicine
item RACIOPPI, LUIGI - Duke University School Of Medicine
item MUKHERJEE, DEBARATI - Duke University School Of Medicine
item ARTHAM, SANDEEP - Duke University School Of Medicine
item GAO, XIA - Children'S Nutrition Research Center (CNRC)
item D'AGOSTINO, LAURA - Bristol-Myers Squibb
item CHANG, CHING-YI - Duke University School Of Medicine
item MCDONNELL, DONALD - Duke University School Of Medicine

Submitted to: Cancer Immunology Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/21/2022
Publication Date: 1/3/2023
Citation: Juras, P.K., Racioppi, L., Mukherjee, D., Artham, S., Gao, X., D'Agostino, L.A., Chang, C., McDonnell, D.P. 2023. Increased CaMKK2 expression is an adaptive response that maintains the fitness of tumor-infiltrating natural killer cells. Cancer Immunology Research. 11(1):109-1022. https://doi.org/10.1158/2326-6066.CIR-22-0391.
DOI: https://doi.org/10.1158/2326-6066.CIR-22-0391

Interpretive Summary: This paper studies an enzyme called calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) that is important in various immune cells. CaMKK2 has been studied in tumor cells and different types of immune cells including macrophages and myeloid cells. Due to the known functions of CaMKK2 in these cells, there is interest in targeting CaMKK2 for anti-tumor therapy. However, the tumor microenvironment is complicated and composed of other types of immune cells. We focused on the importance of CaMKK2 function as a killer of tumor cells. Further we revealed that the acid environment is the driver for CaMKK2 expression in these natural killer cells.

Technical Abstract: Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in a few cell types. Expression of CaMKK2 in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been surging interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. The gap of knowledge in the drug development is that the roles of CaMKK2 in other cellular compartments within the tumor microenvironment remain unclear. Here we studied CaMKK2 in natural killer (NK) cells. We found the basal expression of CaMKK2 is low in NK cells but is upregulated in tumor-infiltrating NK cells. NK cell-intrinsic deletion of CaMKK2 increased metastatic progression in several murine models, establishing a critical role for this enzyme in NK cell-mediated antitumor immunity. Ablation of the CaMKK2 protein, but not inhibition of its kinase activity, resulted in decreased NK-cell survival. Finally, we determined that intracellular lactic acid is a key driver of CaMKK2 expression, suggesting that upregulated expression of this enzyme is an adaptive mechanism by which tumor-infiltrating NK cells mitigate the deleterious effects of a lactic acid-rich tumor microenvironment. The findings of this study indicate an important scaffolding function for CaMKK2 in NK cells, and should inform strategies to manipulate the CaMKK2-signaling axis as a therapeutic approach in cancer.