Cancer cells induce a self-amplifying loop of splenic myelopoiesis in the mouse

Abstract Individuals with cancer often show abnormal hematopoiesis that contributes to the formation of tumor-associated immune cells and tumor microenvironment. We here showed that in lymphoma-bearing mice, hematopoietic stem/progenitor cells (HSPCs) underwent a significant expansion in the spleen, and preferentially differentiated into myeloid lineage, predominantly the myeloid-derived suppressor cells (MDSCs). The myelopoiesis-skewing differentiation program depended on tumor environment, because HSPCs from tumor-free (healthy) donors also underwent myelopoiesis-skewing differentiation in tumor-bearing hosts, and HSPCs from tumor-bearing donors can give rise to a less skewed differentiation spectrum of cell lineages in tumor-free hosts. Furthermore, we tested whether MDSCs (or other myeloid cells) and HSPCs formed a positive feedback loop in driving myelopoiesis. We found that donor MDSCs were able to facilitate the expansion of HSPC population in the spleen in tumor-bearing hosts. The donor MDSCs, however, quickly lost their original phenotype in the hosts and a proportion of them became macrophage-like cells (F4/80+) in the spleen. Depletion of macrophage-like cells, but not MDSCs, strikingly attenuated the generation of HSPCs in tumor-bearing hosts, suggesting that MDSCs may only indirectly contribute to splenic hematopoiesis. Our results provide a paradigm that depicts the cancer-associated abnormalities in hematopoiesis, an important aspect of cancer progression.