Tumor-educated monocyte-dendritic progenitors promote a metastatic switch

Abstract

Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the bone marrow (BM) compartment, their education, immune memory and their differentiation pattern from uncommitted hematopoietic stem cells (HSCs) have not been explored. Here we show that metastatic tumors dictate a unique differentiation pattern of uncommitted HSCs towards myeloid progeny. Single cell RNA-sequencing analysis integrated with proteomic screen of tumor secretome revealed that HSCs differentiate into monocyte-dendritic progenitors (MDP) in highly metastatic tumors but not in low-metastatic tumors which display HSC differentiation into granulocyte-monocyte progenitors (GMP). This effect is driven by IL-6/IL-6R axis which is highly active in metastatic tumors. Consequently, loss and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Consistently, MDPs but not GMPs obtained from highly metastatic tumors, adoptively transferred into mice bearing tumors resulted in increased metastasis. Our study reveals a unique tumor-BM crosstalk that dictates a specific long-lived education of HSCs towards myeloid differentiation, thereby promoting the enrichment of metastasis-associated immune cells in the tumor microenvironment.

Reactive myelopoiesis and FX-expressing monocyte-derived macrophages triggered by chemotherapy promote cancer lung metastasis

“…In contrast, administration of LPS produced neutrophils and monocytes directly from granulocyte-monocyte progenitors (GMP) (52). Further, tumor cells with high metastatic potential enrich MDPs that functionally differentiated into immunosuppressive monocytes to support the metastatic switch (51). Our future study will investigate the effect of chemotherapy treatment on the GMP and MDP.…”

“…In this study, we showed that GEM, PTX, or PTX plus DOX treatment results in myelopoiesis leading to enhanced development of monocytes, but not neutrophils. The difference in myeloid cell development might be due to the different progenitor cells (51,52). For example, in response to CpG-DNA, monocyte-DC progenitors (MDPs) yielded monocytes and dendritic cells.…”

Multiple influence of immune cells in the bone metastatic cancer microenvironment on tumors

“…In metastatic bone cancer, DC in the TME inhibit the tumor-killing activity of CD8+ T cells by producing cytokines such as IL-10, VEGF, TGF-b, and NO (125). IL-6 produced by tumor cells can contribute to the differentiation of hematopoietic stem and progenitor cells (HSPC) into monocyte-dendritic progenitor cells (MDPs) (126). Furthermore, high expression of CD1a(+) and CD83 (+) has been reported to be negatively correlated with the development of bone metastases (127).…”