Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells

Abstract

A major barrier to effective cancer immunotherapy is immune suppression in favor of tumor progression. Additionally, the accumulation of myeloid-derived suppressor cells (MDSCs) has recently been recognized as a major mechanism of the promotion of immune suppression. However, how MDSCs are induced and the cells from which they arise remains unknown. Although studies have demonstrated that tumor-derived cytokines promote MDSC accumulation and activation, little is known regarding the role of the tumor stroma in MDSC accumulation and activation. In this study, we identified a novel mechanism of MDSC differentiation. Tumor-associated fibroblasts (TAFs) attracted monocytes by the stromal cell-derived factor (SDF)-1a/CXCR4 pathway and induced their differentiation into MDSCs through interleukin (IL)-6-mediated STAT3 activation. TAF-treated monocytes (T-MDSCs) then impaired T-cell proliferation and altered the phenotype and/or function of T-cells in an STAT3-dependent manner. CD11b myeloid cells, which resembled T-MDSCs both phenotypically and functionally, were primarily in the peritumoral stroma and a positive association with TAFs in vivo. Additionally, a negative association between CD11b myeloid cell densities and overall survival was observed. An increased number of stromal CD11b myeloid cells was correlated with Hepatocellular Carcinoma (HCC) progression. Together, our results are the first to show that TAF-derived cytokines, such as IL-6 and SDF-1a, can induce MDSC generation and activation and then impair human anti-tumor immune responses, which create favorable conditions for HCC progression. These data also suggest an important role for STAT3 activation in TAF-mediated MDSC generation and MDSC-mediated immune suppression. Consequently, methods in which immunotherapy is combined with IL-6, SDF-1a or STAT3 inhibition may offer an improved option to eliminate suppressive CD11b myeloid cells in HCC patients.

Jianpi Huayu Decoction Attenuates the Immunosuppressive Status of H22 Hepatocellular Carcinoma-Bearing Mice: By Targeting Myeloid-Derived Suppressor Cells

“…Though the immunosuppressive environment formed by liver reduced the antigen recognition by immune cells (Jakab, 2015), but on the contrary, hindered the recognition of mutational cells. Homoplastically, tumor-induced MDSCs could significantly promote progression of tumor, by elaborately establishing immunosuppressive environment (Deng et al, 2017). According to surface markers, MDSCs in mice could be divided into the granulocytic and monocytic MDSC, both which possessed strong immunosuppressive ability (Fleming et al, 2018).…”

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

“…73 CAFs could attract monocytes and further differentiate them into MDSCs via activating STAT3 mediated by IL-6, which creating an immunosuppression microenvironment by inhibiting T cell proliferation in hepatocellular carcinoma. 74 Yang et al reported that FAP + CAFs secreted CCL2 to promote tumour growth via the recruitment of MDSCs in a murine liver tumour model. 75 Multiple studies have shown an anti-tumour effect of inhibiting the colony-stimulating factor 1 receptor (CSF1R).…”

Progressive Enrichment of Stemness Features and Tumor Stromal Alterations in Multistep Hepatocarcinogenesis

“…Interestingly enough CAFs, which in the present study were significantly enriched with IL-6-positive stromal cells particularly in advanced and poorly differentiated HCCs, have been recently shown to make the HCC microenvironment more tolerogenic, by inducing the generation of myeloid-derived suppressor cells through IL-6-mediated STAT3 activation. These data suggest that the “in situ” analysis of the interaction between hepatic cancer cells and those of the tumoral stroma like CAFs, might be of help in the future to discern HCC with distinct tolerogenic features, for potential therapeutic applications [26]. …”