Disruption of SLFN11 Deficiency–Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti–PD-1 Therapy Efficacy in Hepatocellular Carcinoma

Zhou, Chixing; Weng, Juyang; Liu, Chunxiao; Liu, Shaoqing; Hu, Zhiqiu; Xie, Xiaoli; Gao, Dongmei; Zhou, Qiang; Sun, Jialei; Xu, Ru-Chen; Li, Hui; Shen, Ying‐Hao; Ye, Yi; Shi, Yi; Sheng, Xia; Dong, Qiongzhu; Hung, Mien‐Chie; Ren, Ning

doi:10.1053/j.gastro.2023.02.005

Cited by 33 publications

(17 citation statements)

References 49 publications

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“…The combination of targeting macrophages and anti–PD-1 therapy in cancers has been investigated in vitro and in vivo ( 37 , 70 – 72 ). As we have noted above, repolarization of TAM was considered as a promising strategy for cancer treatment and this approach can potentiate anti–PD-1 therapy efficacy in hepatocellular carcinoma ( 72 ). Chemotherapy and radiotherapy may reset macrophages toward a M1 phenotype and improve the efficacy of immunotherapy in cancer ( 71 ).…”

Section: Targeting Macrophages In the Tumor Microenvironmentmentioning

confidence: 99%

New insights into the role of macrophages in cancer immunotherapy

Zhou,

Zhao,

Zhang

et al. 2024

Front. Immunol.

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Macrophages are the main component of the tumor microenvironment, which are differentiated from monocytes in the blood and play an important role in cancer development. Tumor-associated macrophages (TAMs) can promote tumor growth, invasion, metastasis, and resistance to anti–programmed death receptor 1 therapy by regulating programmed cell death ligand 1 expression and interacting with other immune cells in the tumor microenvironment. However, when activated properly, macrophages can also play an anti-tumor role by enhancing the phagocytosis and cytotoxicity of tumor cells. TAM is associated with poor prognosis and drug resistance in patients treated with immunotherapy, indicating that macrophages are attractive targets for combined therapy in cancer treatment. Combination of targeting TAMs and immunotherapy overcomes the drug resistance and achieved excellent results in some cancers, which may be a promising strategy for cancer treatment in the future. Herein, we review the recent findings on the role of macrophages in tumor development, metastasis, and immunotherapy. We focus mainly on macrophage≥centered therapy, including strategies to deplete and reprogram TAMs, which represent the potential targets for improving tumor immunotherapy efficacy.

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Section: Targeting Macrophages In the Tumor Microenvironmentmentioning

confidence: 99%

New insights into the role of macrophages in cancer immunotherapy

Zhou,

Zhao,

Zhang

et al. 2024

Front. Immunol.

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“…M2 exos facilitated CD11b/CD18 intercellular transfer, stimulating the matrix metalloproteinase‐9 signaling pathway in recipient HCC cells to enhance tumor migration (Wu, Gao, et al, 2021). Moreover, in HCC, cells, the knockdown of SLFN1 could promote the macrophage migration and M2‐like polarization in a C‐C motif chemokine ligand 2‐dependent manner, which increased their own PD‐L1 expression via the nuclear factor‐B route (Zhou et al, 2023). Notably, the relative infiltration proportions of Macrophages.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast activation protein promotes progression of hepatocellular carcinoma via regulating the immunity

Wang,

Niu,

Yang

et al. 2024

Cell Biology International

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Fibroblast activation protein (FAP) has been indicated to express in cancer‐associated fibroblasts (CAFs) in most cancers. This work was dedicated to exploring FAP's effects on hepatocellular carcinoma (HCC). The data were extracted from The Cancer Genome Atlas, Gene Expression Omnibus, ImmPort, and Reactome databases. The correlation between FAP and HCC patients' prognosis was explored via survival analysis. The qRT‐PCR and western blot analysis were used to analyze the FAP mRNA and protein expression levels, respectively. The cell proliferation and apoptosis were determined using the cell counting kit‐8 assay kit and Annexin V‐FITC/PI apoptosis kit, respectively. The HCC patients with FAP overexpression displayed a worse prognosis. The FAP expression was positively associated with the infiltration levels of tumor purity, B cell, CD8 + T cell, CD4 + T cell, macrophage, neutrophil, and dendritic cell. The optimal nine immune related genes were screened between two groups (FAP high vs. low). Moreover, we identified 24 energy metabolism related genes (FAP high vs. low) and these 24 genes were highly expressed in the high FAP expression group. The FAP expression had a significant positive correlation with the expression of PD‐1, CTLA4, PDL‐1, and PDL‐2. The FAP overexpression promoted proliferation and migration while inhibiting the apoptosis of HCC cells. The FAP overexpression promoted the progression of HCC by regulating the immunity to affect the prognosis of HCC patients, thereby serving as a poor prognostic marker for HCC patients.

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“…Macrophages are the most abundant mesenchymal cells in HCC, and macrophage polarization plays a signi cant regulatory role in HCC progression . [41,42] We speculated that the release of 27HC induced by TMEM147 may further orchestrate the polarization of TAMs; therefore, we altered the expression of TMEM147 and 27HC, and cultured macrophages with CM from the treated HCC cells to simulate the TME in vivo. Finally, consistent with our hypothesis, HCC cell-derived 27HC signi cantly increased the M2 polarization, which further con rmed the potential mechanism of TMEM147 in HCC cells that TMEM147 in uenced TAM M2 polarization by regulating the release of 27HC.…”

Section: Discussionmentioning

confidence: 99%

TMEM147 aggravates the progression of HCC by modulating cholesterol homeostasis, suppressing ferroptosis, and promoting M2 polarization of TAMs

Huang,

Pan,

Sun

et al. 2023

Preprint

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Background: The endoplasmic reticulum (ER) regulates critical processes, including lipid synthesis, which can be affected by transmembrane proteins localized in the ER membrane. One of them, the transmembrane protein 147 (TMEM147) has been recently implicated for its role in hepatocellular carcinoma (HCC) tumorigenesis, though the mechanisms remain unclear. Here, we investigated the role of TMEM147 in HCC and its underlying mechanisms. Methods: Expression of TMEM147 was examined in human HCC and adjacent non-tumorous tissues using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effects of TMEM147 on HCC progression were investigated both in vitro and in vivo. Proteins interacting with TMEM147 were identified using RNAseq analysis, immunoprecipitation, and mass spectrometry analyses. Lipidomic analysis and enzyme-linked immunosorbent assay (ELISA) were employed to identify and analyze cholesterol and 27-hydroxycholesterol (27HC) contents. Comprehensive experimental methods were used to demonstrate ferroptosis in HCC cells. The fatty acid content of macrophages affected by TMEM147 was quantified using ELISA. Macrophage phenotypes were determined using various assays, such as immunofluorescence assay and flow cytometry analysis. Results: TMEM147 mRNA and protein levels were upregulated in HCC, and increased TMEM147 expression was associated with poor survival. TMEM147 promoted tumor cell proliferation and metastasis in vitro and in vivo. It was found to interact with the key sterol reductase DHCR7, which affected cellular cholesterol homeostasis and increased extracellular 27HC levels in HCC. TMEM147 promoted the expression of DHCR7 by enhancing the activity of the transcription factor, STAT2. 27HC upregulated the expression of glutathione peroxidase 4 in HCC, leading to ferroptosis resistance and promotion of HCC proliferation. HCC cell-derived 27HC activated PPARγ signaling and enhanced lipid metabolism in macrophages, thereby activating M2 polarization, and then promoted the invasion and migration of HCC. Conclusions: Our results indicated that TMEM147 confers ferroptosis resistance and M2 macrophage polarization, which are mainly dependent on the upregulation of cellular cholesterol homeostasis and 27HC secretion, leading to cancer growth and metastasis. Our findings suggest that the TMEM147/STAT2/DHCR7/27HC axis in the tumor microenvironment may serve as a promising therapeutic target for HCC.

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Disruption of SLFN11 Deficiency–Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti–PD-1 Therapy Efficacy in Hepatocellular Carcinoma

Cited by 33 publications

References 49 publications

New insights into the role of macrophages in cancer immunotherapy

New insights into the role of macrophages in cancer immunotherapy

Fibroblast activation protein promotes progression of hepatocellular carcinoma via regulating the immunity

TMEM147 aggravates the progression of HCC by modulating cholesterol homeostasis, suppressing ferroptosis, and promoting M2 polarization of TAMs

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