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; Donald P McDonnell

doi:10.1038/s41467-019-10424-5

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

Nat Commun. 2019 Jun 4;10(1):2450. doi: 10.1038/s41467-019-10424-5.

Authors

Luigi Racioppi^{1

2}, Erik R Nelson^{3

4

5}, Wei Huang⁶, Debarati Mukherjee⁷, Scott A Lawrence^{7

8}, William Lento⁶, Anna Maria Masci⁹, Yiquin Jiao⁶, Sunghee Park⁷, Brian York^{10

11}, Yaping Liu⁶, Amy E Baek³, David H Drewry^{12

13}, William J Zuercher^{12

13}, Francesca R Bertani¹⁴, Luca Businaro¹⁴, Joseph Geradts^{15

16}, Allison Hall¹⁶, Anthony R Means^{10

11}, Nelson Chao⁶, Ching-Yi Chang⁷, Donald P McDonnell¹⁷

Affiliations

¹ Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, NC, 27710, USA. [email protected].
² Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, 80131, Italy. [email protected].
³ Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
⁴ University of Illinois Cancer Center, Chicago, IL, 60612, USA.
⁵ Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
⁶ Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, NC, 27710, USA.
⁷ Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
⁸ Eli Lilly and Company, Indianapolis, IN, 46285, USA.
⁹ Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, 27710, USA.
¹⁰ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
¹¹ Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
¹² Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, NC, 27709, USA.
¹³ UNC Eshelman School of Pharmacy, Chapel Hill, NC, 27599, USA.
¹⁴ CNR IFN Institute for Photonics and Nanotechnologies, Rome, 00156, Italy.
¹⁵ Department of Population Sciences, City of Hope National Medical Center, Duarte, CA, 91010, USA.
¹⁶ Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
¹⁷ Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Breast Neoplasms / genetics
Breast Neoplasms / immunology*
Breast Neoplasms / metabolism
CD8-Positive T-Lymphocytes / immunology
Calcium-Calmodulin-Dependent Protein Kinase Kinase / antagonists & inhibitors
Calcium-Calmodulin-Dependent Protein Kinase Kinase / genetics
Calcium-Calmodulin-Dependent Protein Kinase Kinase / immunology*
Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
Carcinoma / genetics
Carcinoma / immunology*
Carcinoma / metabolism
Cell Proliferation
Chemokines / immunology
Female
Humans
Immunohistochemistry
In Vitro Techniques
Macrophages / immunology
Macrophages / metabolism
Mammary Neoplasms, Animal / genetics
Mammary Neoplasms, Animal / immunology*
Mammary Neoplasms, Animal / metabolism
Mice
Mice, Knockout
Mice, Transgenic
Myeloid Cells / immunology*
Myeloid Cells / metabolism
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / immunology
Triple Negative Breast Neoplasms / metabolism
Tumor Escape / genetics
Tumor Escape / immunology*
Tumor Microenvironment / immunology*

Substances

Chemokines
CAMKK2 protein, human
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Camkk2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding