B-cell derived macrophage in mouse and human breast cancer macrophage

Cancer actively uses B cells to promote its progression and metastasis. For example, it causes accumulation of bone marrow (BM) B-cell precursors in spleen to convert into immunosuppressive Breg cells. Here, we provide evidence that cancer also coopts differentiation BM CSF1R+ Pax5Lo B-cell precursors to generate macrophages (termed B-MF cells). To do this, cancer uses CSF1 to trigger Csf1r signaling and downregulate PAX5 in B-cell precursors by activating FOXO1. Although tumor-associated macrophages (TAMs) are primarily derived from BM monocytes, our data suggest that some of them may have B-cell origin. Unlike monocyte-derived TAMs, B-MF exhibit a higher M2 polarization, more efficiently phagocytize apoptotic cells, induce FoxP3+ Tregs and suppress T cells activity. We propose that the cancer-B-MF axis is a novel immune escape pathway, thus a therapeutic target. Overall design: mouse ATAC-seq was performed to compare the open chromatin regions between Csf1r+ BM and Csf1r- BM/ Csf1r+Spleen and Csf1r- Spleen. We also performed scRNA-seq using invitro/invivo tumor macrophage samples.