Abstract
Hepatic stellate cells (HSCs) are critical mediators of immunosuppression and the pathogenesis of hepatocellular carcinoma (HCC). Our previous work indicates that HSCs promote HCC progression by enhancing immunosuppressive cell populations including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). MDSCs are induced by inflammatory cytokines (e.g., prostaglandins) and are important in immune suppression. However, how HSCs mediate expansion of MDSCs is uncertain. Thus, we studied activated HSCs that could induce MDSCs from bone marrow cells and noted that HSC-induced MDSCs up-regulated immunosuppressive activity via iNOS, Arg-1, and IL-4Rα. After treating cells with a COX-2 inhibitor or an EP4 antagonist, we established that HSC-induced MDSC accumulation was mediated by the COX2-PGE2-EP4 signaling. Furthermore, in vivo animal studies confirmed that inhibition of HSC-derived PGE2 could inhibit HSC-induced MDSC accumulation and HCC growth. Thus, our data show that HSCs are required for MDSC accumulation mediated by the COX2-PGE2-EP4 pathway, and these data are the first to link HSC and MDSC subsets in HCC immune microenvironment and provide a rationale for targeting PGE2 signaling for HCC therapy.
Highlights
Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the third leading cause of cancer-related deaths around the world [1, 2]
The expression of dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and MDSC subsets were detected after bone marrow (BM) cells were cultured with Hepatic stellate cells (HSCs)-CM
To verify the specific HSC-conditioned medium (HSC-CM) effect on MDSC expansion, we used CM from MEF cells as controls and noted that MEF-CM had no effect on MDSC expansion, and the influence of HSC-CM on BM cells was concentration-dependent (Figure 1D)
Summary
Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the third leading cause of cancer-related deaths around the world [1, 2]. Infiltrating stromal and immune cells in the tumor microenvironment contribute to cancer biology as well [3]. Hepatic stellate cells (HSCs) are important stromal cells that are activated during liver injury, inflammation, infection, trauma, or by other pathogens [4, 5]. We reported that activated HSCs can induce immune-suppressing cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in tissues of tumor-bearing mice [810]. MDSCs are heterogeneous immature myeloid cells comprised of myeloid progenitors and precursors of macrophages, granulocytes, and dendritic cells (DCs) [11, 12]. Murine MDSCs co-express CD11b and Gr-1 [11] and their heterogeneity is based on expression of Gr-1: granulocytic-MDSCs (G-MDSCs, CD11b+Ly6G+Ly6Cint/ low), and monocytic-MDSCs (Mo-MDSCs, CD11b+ Ly6G-Ly6Chigh) [13, 14]. Höchst’s group reported that activated HSCs can recruit and transform peripheral blood monocytes into de novo MDSCs [15] but how HSCs induce MDSC expansion and activation is unclear
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