Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils

Significance We show that tumor reprogramming of hematopoiesis in bone marrow occurs at the onset of malignant conversion and results in systemic expansion of circulating activated neutrophils that preferentially accumulate in lungs. Our data are, to our knowledge, the first to show that activation and not inhibition of myeloid differentiation is responsible for expansion and activity of T cell-suppressive myeloid cells; a tumor-derived factor targets the immature hematopoietic compartment to drive myeloid expansion; granulocyte-colony stimulating factor (G-CSF) is the only hematopoietic growth factor to increase in serum during early tumor development; prolonged G-CSF induces production of Rb1 low neutrophils and not short-term mobilization; and G-CSF acts in a cell intrinsic manner to expand multipotent progenitors to increase production of tumor-derived Ly6G + neutrophils.