biostudies-literatureUnknown14(2)Lian SLThe inflammation-related tumor microenvironment (TME) is one of the major driving forces of hepatocarcinogenesis. We aimed to investigate cell-to-cell communication among Hepatocellular Carcinoma (HCC) through re-analyzing HCC single-cell RNA-seq data, and to confirm such cellular interaction through <i>in vitro</i> and <i>in vivo</i> study. We found a subset of Regulatory B cells with PD-L1 expression (PD-L1⁺ Bregs), mainly located in adjacent HCC tissues. In co-localization with PD-L1⁺ Bregs, a subset of Tumor Associated Macrophages with high expression of CXCL12 (CXCL12⁺ TAMs) was also mainly located in adjacent HCC tissues. Moreover, CXCL12⁺ TAMs can be stimulated <i>in vitro</i> using an HCC conditional medium. Using CellChat analysis and Multiplex Immunohistochemistry staining (mIHC), CXCL12⁺ TAMs were found to be first recruited by Cancer-Associated Fibroblasts (CAFs) through a CD74/macrophage migration inhibitory factor (MIF) pattern, and further differentiated into TGF-β-enriched tissues. Furthermore, CXCL12⁺ TAMs recruited PD-L1⁺ Bregs via the CXCL12/CXCR4 axis, and CXCR4 expression was significantly positively correlated to PD-L1 expression in PD-L1⁺ Bregs. At last, we confirmed the communications among CAFs, Macrophages and B cells and their tumor-promoting effects by using an orthotopic mouse model of HCC. Immunosuppressive HCC TME involving cell-to-cell communications comprised MIF-secreting CAFs, CXCL12-secreting TAMs, and PD-L1-producing Bregs, and their regulation could be promising therapeutic targets in future immunotherapy for human HCC.American journal of cancer research832-853https://www.ebi.ac.uk/biostudies/studies/S-EPMC10915331biostudies-literatureTumor-associated macrophages promoting PD-L1 expression in infiltrating B cells through the CXCL12/CXCR4 axis in human hepatocellular carcinoma.PMC10915331Lian SLWang XLYao YLLu YTLu YJJiang RQfalseTumor-associated macrophages promoting PD-L1 expression in infiltrating B cells through the CXCL12/CXCR4 axis in human hepatocellular carcinoma.The inflammation-related tumor microenvironment (TME) is one of the major driving forces of hepatocarcinogenesis. We aimed to investigate cell-to-cell communication among Hepatocellular Carcinoma (HCC) through re-analyzing HCC single-cell RNA-seq data, and to confirm such cellular interaction through <i>in vitro</i> and <i>in vivo</i> study. We found a subset of Regulatory B cells with PD-L1 expression (PD-L1⁺ Bregs), mainly located in adjacent HCC tissues. In co-localization with PD-L1⁺ Bregs, a subset of Tumor Associated Macrophages with high expression of CXCL12 (CXCL12⁺ TAMs) was also mainly located in adjacent HCC tissues. Moreover, CXCL12⁺ TAMs can be stimulated <i>in vitro</i> using an HCC conditional medium. Using CellChat analysis and Multiplex Immunohistochemistry staining (mIHC), CXCL12⁺ TAMs were found to be first recruited by Cancer-Associated Fibroblasts (CAFs) through a CD74/macrophage migration inhibitory factor (MIF) pattern, and further differentiated into TGF-β-enriched tissues. Furthermore, CXCL12⁺ TAMs recruited PD-L1⁺ Bregs via the CXCL12/CXCR4 axis, and CXCR4 expression was significantly positively correlated to PD-L1 expression in PD-L1⁺ Bregs. At last, we confirmed the communications among CAFs, Macrophages and B cells and their tumor-promoting effects by using an orthotopic mouse model of HCC. Immunosuppressive HCC TME involving cell-to-cell communications comprised MIF-secreting CAFs, CXCL12-secreting TAMs, and PD-L1-producing Bregs, and their regulation could be promising therapeutic targets in future immunotherapy for human HCC.2024-01-01T00:00:00Z20242026-06-26T03:12:33.816Z2026-06-26T03:07:10.62ZS-EPMC109153313845542010.62347/ziax8828