Spleen actively recruits, maintains and expands hematopoietic stem and progenitor cells in tumor-bearing hosts

Abstract

Abstract We recently found that circulating hematopoietic stem and progenitor cells (HSPC) from various cancer patients exhibit a generalized myeloid bias with a skew toward granulocytic differentiation. These circulating myeloid precursors are highly enriched in tumors and serve as an important link between dysregulated hematopoiesis and accumulated myeloid-derived suppressor cells (MDSC) in cancer patients. Here, we showed that, in various murine tumor models, spleen is significantly superior to bone-marrow in inducing expansion of both hematopoietic stem cells and discrete intermediary progenitors, with a skew toward myelopoiesis. The bone-marrow derived HSPC are actively recruited and maintained in the spleen of tumor-bearing mice, a process that is regulated by CCL2/CCR2 axis, but not CXCL12. Splenic HSPC from tumor-bearing mice exhibits significantly higher proliferative activity and gives rise to CD11b+Gr-1intLy6G− Ly6Chi multipotent monocytic cells, the committed progenitors and immediate precursors of MDSC. Accordingly, abrogation of splenic hematopoiesis synergistically enhanced the therapeutic efficacy of anti-PD-L1 treatment. Moreover, we found that hematopoietic precursors and myeloid cells are accumulated in the spleen of patients with various solid tumors. These data suggest that the spleen is an important extramedullary reservoir and source of myeloid progenitors. Identifying unique splenic signals that instruct myeloid cells and their precursors might provide a novel strategy for anticancer therapy.