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

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

PROVIDER: PRJNA416369 | ENA |

REPOSITORIES: ENA

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

Project description:Tumor-associated myeloid cells play a pivotal role in the regulation of processes that control tumor growth and metastasis, and their accumulation in tumors is an established negative prognostic factor in breast cancer. Here, we show that inhibition of calcium/calmodulin-dependentkinase kinase 2 (CaMKK2) expression within myeloid cells inhibits tumor growth in mouse models of mammary cancer. This activity is associated with the accumulation of macrophages within the tumor microenvironment that express high levels of the major histocompatibility molecule class II molecule I-A (MHC II I-A), and granzyme positive CD8+T-cells. Treatment with specific CaMKK2 inhibitors block tumor growth, in a CD8+ T-cell dependent manner, and facilitates favorable reprogramming of the immune cell microenvironment. CaMKK2 protein expression was highest in the most aggressive subtypes of human breast cancer and, in the most malignant tumors, both tumor cells and tumor-associated macrophages express high levels of this enzyme. In aggregate, these findings implicate CaMKK2 as a macrophage-selective immune checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.

2019-06-16 | GSE106357 | GEO

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

Project description: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.

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