E-105 Mesenchymal stromal cells: Mediators of inflammation in cancer

Abstract

Cancer-associated fibroblasts (CAF) have been identified in the tumor microenvironment (TME) of many cancers. CAF represent a heterogeneous population of cells that can have pro-tumorigenic and anti-tumorigenic functions. We have isolated from primary human neuroblastoma tumors, a population of CAF that share phenotypic and functional characteristics of bone marrow-derived mesenchymal stromal cells (MSC). These cells are CD73+, CD90+, CD105+, CD34−, CD45−, CD14−, CD19−, CD31−, and VEGFR2−, and retain the ability to differentiate into osteoblasts, chondrocytes and adipocytes, a feature of MSC. However, we show that these cells also express fibroblast activation protein alpha (FAP/DPPIV), fibroblast specific protein 1 (FSP1/S1004A) and alpha smooth muscle actin (SMA), markers of cancer-associated fibroblasts. When in the presence of tumor cells, these MSC/CAF stimulate the production of multiple pro-tumorigenic cytokines and chemokines including interleukin (IL)-6, IL-8, CCL2/monocyte chemoattractant protein 1, CXCL-12/stromal-derived factor 1 (SDF1), CXCL1, vascular endothelial growth factor (VEGF-A), plasminogen activator inhibitor 1 (PAI-1) and transforming growth factor (TGF) β. The production of these cytokines/chemokines by MSC/CAF is stimulated by the production of soluble factors by tumor cells including galectin-3 binding protein and extracellular vesicles. In addition to stimulating angiogenesis, the recruitment and M2 polarization of macrophages, and to suppress immune cells, MSC/CAF have a direct effect on tumor cells by stimulating tumor cell growth, survival and resistance to chemotherapy in an ERK1/2 and STAT3-dependent manner. We then show that targeting ERK1/2 and STAT3 or targeting MSC in combination with chemotherapy or immunotherapy in mice orthotopically implanted with human neuroblastoma tumors, inhibits tumor growth and extends survival. In contrast, targeting a single cytokine like IL-6 has no significant effect. These data thus identify a new type of CAF sharing characteristics of bone marrow-derived MSCs that contribute to a pro-tumorigenic inflammatory reaction in the TME and provide preclinical evidence that targeting these cells or the pathways they activated in tumor cells is a valuable therapeutic approach.