Endothelial ACKR1 expression regulates neutrophil infiltration and breast cancer metastatic engraftment in the lung metastatic niche

The formation of the premetastatic niche prepares distant tissues for tumor cell engraftment. Endothelial cells are critical mediators of premetastatic niche formation, orchestrating extravasation of circulating tumor cells and critical pro-tumor immune cells, such as neutrophils. In mouse models of breast cancer, we show that primary tumors upregulate the non-signaling chemokine receptor ACKR1 in the endothelium of the lung premetastatic niche. ACKR1-expressing venules were found to be preferential sites of neutrophil and tumor cell localization within lung tissue. A newly generated conditional ACKR1 allele was used to show that endothelial-specific removal of ACKR1 expression significantly reduces metastatic engraftment in the lung. When ACKR1 is activated by tumor-secreted factors, endothelial ACKR1 functions to promote neutrophil recruitment within the lung parenchyma. We conclude that ACKR1 is a critical component of the endothelial response to tumors at the metastatic site of the lung, leading to neutrophil recruitment and promotion of tumor cell metastasis. SUMMARYEndothelial cells play critical roles in breast cancer metastasis. ACKR1 is upregulated in the endothelium of the lung metastatic niche in response to primary mammary tumors. Endothelial ACKR1 expression was found to promote neutrophil infiltration into the metastatic niche and support breast tumor cell metastasis to the lung.