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DAB2+ macrophages support FAP+ fibroblasts in shaping tumor barrier and inducing poor clinical outcomes in liver cancer.

ABSTRACT: Background: Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. Methods: A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. Results: Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). FAP+ fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The DAB2+ and SPP1+ tumor-associated macrophages (TAMs) reinforce the function of FAP+ CAFs through signals such as TGF-β, PDGF, and ADM. Notably, the interaction between DAB2+ TAMs and FAP+ CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. Conclusions: The interaction between DAB2+ TAMs and FAP+ CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of FAP+ CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.

SUBMITTER: Long F

PROVIDER: S-EPMC11373629 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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DAB2 + macrophages support FAP + fibroblasts in shaping tumor barrier and inducing poor clinical outcomes in liver cancer.

Long Fei F Zhong Wei W Zhao Faming F Xu Yaqi Y Hu Xin X Jia Gaihua G Huang Lanxiang L Yi Kezhen K Wang Na N Si Huaqi H Wang Jun J Wang Bicheng B Rong Yuan Y Yuan Yufeng Y Yuan Chunhui C Wang Fubing F

Theranostics 20240812 12

Background: Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. Methods: A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexiti ...[more]

PMID: 39239526

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Project description:ObjectiveThis study aimed to explore the clinical significance of CD45+CD33+CD14-CD10-HLA-DR-/low neutrophils (Cluster of Differentiation 10 [CD10-] neutrophils) in B-cell non-Hodgkin's lymphoma (B-NHL). An amplification system of CD10- neutrophils in vitro was constructed using cytokines, and the mechanisms underlying the cytokine-induced expansion and activation of the CD10- neutrophil subpopulation were investigated.Material and methodsWe identified a novel suppressive cell population known as CD10- neutrophils in the peripheral blood of patients with B-NHL in different statuses by flow cytometry and found it to be correlated with interleukin-6 levels, T cell counts, and plasma arginase-1 (Arg-1) levels. We then verified the effect of CD10- neutrophil expression on the prognosis of patients with B-NHL. Furthermore, we described a clinically compatible method for generating granulocyte populations rich in CD10- neutrophils using cultures of peripheral blood-isolated neutrophils supplemented with cytokines in vitro. Arg-1 expression was detected in neutrophils before and after induction by cytokines through reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and flow cytometry. T-cell proliferation and apoptosis were measured by carboxyfluorescein succinimidyl ester assay and Annexin V-Propidium Iodide stains, and induced cells were exposed to Arg-1 inhibitor and ruxolitinib. signal transducer and activator of transcription 3 (STAT3)/Arg-1 signaling was studied mainly by western blot and chromatin immunoprecipitation experiments.ResultsWe established a correlation between high CD10- neutrophil levels and poorer survival outcomes in patients with B-NHL. Moreover, CD10- neutrophils were positively correlated with interleukin (IL)-6, T-reg cells, and plasma Arg-1 levels and negatively correlated with the absolute number of total T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor, and IL-6 could all induce the expansion of CD10- neutrophil phenotype cells in vitro, which exhibit typical immature cellular morphology, and the combination of IL-6 and GM-CSF was the most effective. We confirmed that the STAT3/Arg-1 signaling pathway could be a critical mechanism regulating CD10- neutrophil-mediated immunosuppression in vitro.ConclusionCD10- neutrophils exhibited basic characteristics similar to conventional myeloid-derived suppressor cells. Our observations provide a promising STAT3 or Arg-1 targeting strategy for B-NHL and an important method for generating remarkably amounts of inhibitory granulocyte populations rich in CD10- neutrophils for immunotherapy.

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DAB2+ macrophages support FAP+ fibroblasts in shaping tumor barrier and inducing poor clinical outcomes in liver cancer.

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<i>DAB2</i> <sup>+</sup> macrophages support <i>FAP</i> <sup>+</sup> fibroblasts in shaping tumor barrier and inducing poor clinical outcomes in liver cancer.

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