CaMKK2 in myeloid cells is a key regulator of the immune-suppressive microenvironment in breast cancer

Luigi Racioppi (), Erik R. Nelson, Wei Huang, Debarati Mukherjee, Scott A. Lawrence, William Lento, Anna Maria Masci, Yiquin Jiao, Sunghee Park, Brian York, Yaping Liu, Amy E. Baek, David H. Drewry, William J. Zuercher, Francesca R. Bertani, Luca Businaro, Joseph Geradts, Allison Hall, Anthony R. Means, Nelson Chao, Ching-yi Chang and Donald P. McDonnell ()
Additional contact information
Luigi Racioppi: Division of Hematological Malignancies and Cellular Therapy, Duke University School of Medicine
Erik R. Nelson: Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign
Wei Huang: Division of Hematological Malignancies and Cellular Therapy, Duke University School of Medicine
Debarati Mukherjee: Duke University School of Medicine
Scott A. Lawrence: Duke University School of Medicine
William Lento: Division of Hematological Malignancies and Cellular Therapy, Duke University School of Medicine
Anna Maria Masci: Duke University
Yiquin Jiao: Division of Hematological Malignancies and Cellular Therapy, Duke University School of Medicine
Sunghee Park: Duke University School of Medicine
Brian York: Baylor College of Medicine
Yaping Liu: Division of Hematological Malignancies and Cellular Therapy, Duke University School of Medicine
Amy E. Baek: Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign
David H. Drewry: GlaxoSmithKline, Research Triangle Park
William J. Zuercher: GlaxoSmithKline, Research Triangle Park
Francesca R. Bertani: CNR IFN Institute for Photonics and Nanotechnologies
Luca Businaro: CNR IFN Institute for Photonics and Nanotechnologies
Joseph Geradts: City of Hope National Medical Center
Allison Hall: Duke University School of Medicine
Anthony R. Means: Baylor College of Medicine
Nelson Chao: Division of Hematological Malignancies and Cellular Therapy, Duke University School of Medicine
Ching-yi Chang: Duke University School of Medicine
Donald P. McDonnell: Duke University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2−/− mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2−/− macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.

Date: 2019
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DOI: 10.1038/s41467-019-10424-5

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