IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells

Abstract

BackgroundMetastasis is the major cause of death in patients with cancer. Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the bone marrow (BM) compartment and their differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) have not been explored.MethodsWe used a unique model system consisting of tumor cell clones with low metastatic potential or high metastatic potential (met-low and met-high, respectively) to investigate the fate of HSPC differentiation using murine melanoma and breast carcinoma. Single-cell RNA sequencing (scRNA-seq) analysis was performed on HSPC obtained from the BM of met-low and met-high tumors. A proteomic screen of tumor-conditioned medium integrated with the scRNA-seq data analysis was performed to analyze the potential cross talk between cancer cells and HSPCs. Adoptive transfer of tumor-educated HSPC subsets obtained from green fluorescent protein (GFP)+ tagged mice was then carried out to identify the contribution of committed HSPCs to tumor spread. Peripheral mononuclear cells obtained from patients with breast and lung cancer were analyzed for HSPC subsets.ResultsMice bearing met-high tumors exhibited a significant increase in the percentage of HSPCs in the BM in comparison with tumor-free mice or mice bearing met-low tumors. ScRNA-seq analysis of these HSPCs revealed that met-high tumors enriched the monocyte-dendritic progenitors (MDPs) but not granulocyte-monocyte progenitors (GMPs). A proteomic screen of tumor- conditioned medium integrated with the scRNA-seq data analysis revealed that the interleukin 6 (IL-6)–IL-6 receptor axis is highly active in HSPC-derived MDP cells. Consequently, loss of function and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Importantly, IL-6-educated MDPs induce metastasis within mice bearing met-low tumors—through further differentiation into immunosuppressive macrophages and not dendritic cells. Consistently, MDP but not GMP levels in peripheral blood of breast and lung cancer patients are correlated with tumor aggressiveness.ConclusionsOur study reveals a new role for tumor-derived IL-6 in hijacking the HSPC differentiation program toward prometastatic MDPs that functionally differentiate into immunosuppressive monocytes to support the metastatic switch.

IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment

“…Magidey-Klein et al. demonstrates IL-6 plays a functional role in mediating crosstalk between primary tumors and the bone marrow to promote monocyte-dendritic progenitors to give rise to immunosuppressive macrophages which, in turn, promotes metastasis in vivo ( 127 ). Whether IL-6 mediates organ-specific breast cancer metastasis remains to be conclusively elucidated.…”

“…For example, tumor secreted IL-6 has been recently reported to enhance metastatic potential through educating monocyte-dendritic progenitors to prime distant organs for breast cancer metastasis. Magidey-Klein et al demonstrates IL-6 plays a functional role in mediating crosstalk between primary tumors and the bone marrow to promote monocyte-dendritic progenitors to give rise to immunosuppressive macrophages which, in turn, promotes metastasis in vivo (127). Whether IL-6 mediates organ-specific breast cancer metastasis remains to be conclusively elucidated.…”

Serum levels of IL-6 and CRP can predict the efficacy of mFOLFIRINOX in patients with advanced pancreatic cancer

“…The relationship between CRP and IL-6 in predicting PFS in patients with mPC should be further explored in future studies. IL-6 induces metastasis through programming hematopoietic stem and progenitor cells toward tumorsupporting metastatic cells (30). Additionally, IL-6 affects monocyte-dendritic progenitors to differentiate into metastasis-promoting cells, thereby promoting tumor aggressiveness (30).…”

“…IL-6 induces metastasis through programming hematopoietic stem and progenitor cells toward tumorsupporting metastatic cells (30). Additionally, IL-6 affects monocyte-dendritic progenitors to differentiate into metastasis-promoting cells, thereby promoting tumor aggressiveness (30). An elevated CRP level may reflect a nonspecific inflammatory response to tumor necrosis, which in turn indicates the levels of inflammatory cytokines such as IL-6.…”

Contribution of immune cells to bone metastasis pathogenesis

“…Evidence indicates that the stem cell released by OCs might trigger the nuclear factor-κB (NF-κB) pathway to induce tumor cell responses ( 12 ). Interleukin (IL)-6 plays a functional role in mediating the crosstalk between primary tumors and the bone marrow to promote monocyte-dendritic progenitors to give rise to immunosuppressive macrophages which, in turn, promote metastasis in vivo ( 13 ). An elementary molecule connected with the immune system and bone is supported by the specific axis involving RANKL, RANKL, and osteoprotegerin ( 14 ).…”