Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells.
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.
Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
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Y
Deng
Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
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J
Cheng
Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
B
B
Fu
Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
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W
Liu
Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
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G
Chen
Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.|Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Q
Zhang
Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
Y
Y
Yang
D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007165:Immunosuppression Therapy; D015850:Interleukin-6 / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor