Dataset Information

Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma.

ABSTRACT:

Background

Hepatocellular carcinoma (HCC) is a malignancy with limited treatment options and poor prognosis. Macrophages are enriched in the HCC microenvironment and have a significant impact on disease progression and therapy efficacy. We aim to identify critical macrophages subsets involved in HCC development.

Methods

Macrophage-specific marker genes were identified through single-cell RNA sequencing analyses. The clinical significance of macrophages with palmitoyl-protein thioesterase 1 (PPT1) positive was investigated in 169 patients with HCC from Zhongshan Hospital using immunohistochemistry and immunofluorescence. The immune microenvironment of HCC and the functional phenotype of PPT1⁺ macrophages were explored using cytometry by time-of-flight (CyTOF) and RNA sequencing.

Results

Single-cell RNA sequencing analyses revealed that PPT1 was predominantly expressed in macrophages in HCC. Intratumoral PPT1⁺ macrophages abundance was associated with inferior survival durations of patients and an independent risk factor of prognosis for HCC. High throughput analyses of immune infiltrates showed that PPT1⁺ macrophage-enriched HCCs were characterized by high infiltration of CD8⁺ T cells with increased programmed death-1 (PD-1) expression. PPT1⁺ macrophages exhibited higher galectin-9, CD172a, and CCR2 levels but lower CD80 and CCR7 levels than PPT1^- macrophages. Pharmacological inhibition of PPT1 by DC661 suppressed mitogen-activated protein kinase (MAPK) pathway activity but activated nuclear factor kappa B (NF-κB) pathway in macrophages. In addition, DC661 enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model.

Conclusions

PPT1 is mainly expressed in macrophages in HCC and promotes immunosuppressive transformation of macrophages and tumor microenvironment. PPT1⁺ macrophage infiltration is associated with poor prognosis of patients with HCC. Targeting PPT1 may potentiate the efficacy of immunotherapy for HCC.

SUBMITTER: Weng J

PROVIDER: S-EPMC10314632 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma.

Weng Jialei J Liu Shaoqing S Zhou Qiang Q Xu Wenxin W Xu Minghao M Gao Dongmei D Shen Yinghao Y Yi Yong Y Shi Yi Y Dong Qiongzhu Q Zhou Chenhao C Ren Ning N

Journal for immunotherapy of cancer 20230601 6

<h4>Background</h4>Hepatocellular carcinoma (HCC) is a malignancy with limited treatment options and poor prognosis. Macrophages are enriched in the HCC microenvironment and have a significant impact on disease progression and therapy efficacy. We aim to identify critical macrophages subsets involved in HCC development.<h4>Methods</h4>Macrophage-specific marker genes were identified through single-cell RNA sequencing analyses. The clinical significance of macrophages with palmitoyl-protein thioe ...[more]

PMID: 37385725

Similar Datasets

Project description:BackgroundAdaptive resistance and side effects of sorafenib treatment result in unsatisfied survival of patients with hepatocellular carcinoma (HCC). Palmitoyl-protein thioesterase 1 (PPT1) plays a critical role in progression of various cancers. However, its role on prognosis and immune infiltrates in HCC remains unclarified.MethodsBy data mining in the Cancer Genome Atlas databases, the role of PPT1 in HCC were initially investigated. Furthermore, HCC cell lines Hep 3B and Hep 1-6 were treated with DC661 or siRNA against PPT1. The biological function of PPT1 was determined by CCK-8 test, colony formation assay, TUNEL staining, immunofluorescence staining, Western blot test, and PI-Annexin V apoptosis assays in vitro. Animal models of subcutaneous injection were applied to investigate the therapeutic role of targeting PPT1.ResultsWe found that PPT1 levels were significantly upregulated in HCC tissues compared with normal tissues and were significantly associated with a poor prognosis. Multivariate analysis further confirmed that high expression of PPT1 was an independent risk factor for poor overall survival of HCC patients. We initially found that PPT1 was significantly upregulated in sorafenib-resistant cell lines established in this study. Upon sorafenib treatment, HCC cells acquired adaptive resistance by inducing autophagy. We found that DC661, a selective and potent small-molecule PPT1-inhibitor, induced lysosomal membrane permeability, caused lysosomal deacidification, inhibited autophagy and enhanced sorafenib sensitivity in HCC cells. Interestingly, this sensitization effect was also mediated by the induction mitochondrial pathway apoptosis. In addition, the expression level of PPT1 was associated with the immune infiltration in the HCC tumor microenvironment, and PPT1 inhibitor DC661 significantly enhanced the anti-tumor immune response by promoting dendritic cell maturation and further promoting CD8+ T cell activation. Moreover, DC661 combined with sorafenib was also very effective at treating tumor models in immunized mice.ConclusionsOur findings suggest that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC.

Dataset Information

Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma.

Background

Methods

Results

Conclusions

Publications

Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma.

Similar Datasets

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