Huiheng Ning

Cancer progression is associated with alterations of intra- and extramedullary hematopoiesis to support a systemic tumor-promoting myeloid response. However, the functional specialty, mechanism, and clinical relevance of extramedullary hematopoiesis (EMH) remain unclear. Here, we showed that the heightened splenic myelopoiesis in tumor-bearing hosts was not only characterized by the accumulation of myeloid precursors, but also associated with profound functional alterations of splenic early hematopoietic stem/progenitor cells (HSPCs). With the distinct capability to produce and respond to granulocyte-macrophage CSF (GM-CSF), these splenic HSPCs were "primed" and committed to generating immunosuppressive myeloid cells. Mechanistically, the CCL2/CCR2 axis-dependent recruitment and the subsequent local education by the splenic stroma were critical for eliciting this splenic HSPC response. Selective abrogation of this splenic EMH was sufficient to synergistically enhance the therapeutic efficacy of immune checkpoint blockade. Clinically, patients with different types of solid tumors exhibited increased splenic HSPC levels associated with poor survival. These findings reveal a unique and important role of splenic hematopoiesis in tumor-associated myelopoiesis.

Schwann cells locate at the leading edge of NI, can be induced by transforming growth factor β (TGF-β) signaling, promote tumor cell migration, and correlate with poor survival. We also identify basal-like and neural-reactive malignant subpopulations with distinct morphologies and heightened NI potential. This landscape depicting tumor-associated nerves highlights critical cancer-immune-neural interactions in situ and enlightens treatment development targeting NI.

We recently identified CXCR4 as a novel vascular marker for vessel sprouting in hepatocellular carcinoma (HCC) tissues. Thus, CXCR4+ endothelial cells (ECs) could serve as a potential predictor for patients who may benefit from sorafenib treatment; however, the mechanism that regulates vascular CXCR4 expression in HCC remains largely unknown. Here, we revealed a large number of monocytes/macrophages (Mo/Mφ) to be selectively enriched in the perivascular areas of CXCR4+ vessels in HCC samples. The depletion of Mo/Mφ with gadolinium chloride (GdCl3) or zoledronic acid (ZA) treatment significantly reduced vascular CXCR4 expression in HCC tumors. This phenomenon was also confirmed in CCR2-KO mice, which exhibited reduced infiltration of inflammatory Mo/Mφ in tumor tissues. Mechanistic studies revealed that inflammatory cytokines derived from tumor conditioned Mo/Mφ, especially TNF-α, could up-regulate CXCR4 expression on ECs. TNF-α-induced activation of the Raf-ERK pathway, but not Notch signaling, was responsible for the expression of CXCR4. Moreover, the combination treatment of sorafenib with ZA was associated with improved anti-tumor efficacy by significantly reducing vascular CXCR4 expression. These findings revealed that Mo/Mφ could regulate CXCR4 expression in the tumor vasculature. Thus, the inhibition of Mo/Mφ inflammation might enhance the treatment efficacy of sorafenib in HCC.

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.