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Disruption of Tumour-Associated Macrophage Trafficking by the Osteopontin-Induced Colony-Stimulating factor-1 Signalling Sensitises Hepatocellular Carcinoma to anti-PD-L1 Blockade

Disruption of Tumour-Associated Macrophage Trafficking by the Osteopontin-Induced Colony-Stimulating factor-1 Signalling Sensitises Hepatocellular Carcinoma to anti-PD-L1 Blockade

Ying Zhu, Jing Yang, Da Xu, Xiao-Mei Gao, Ze Zhang, Jennifer L Hsu, Chia-Wei Li, Seung-Oe Lim, Yuan-Yuan Sheng, Yu Zhang, Jian-Hua Li, Qin Luo, Yan Zheng, Yue Zhao, Lu Lu, Hu-Liang Jia, Mien-Chie Hung, etc.

Gut. 2019 Sep;68(9):1653-1666.

PMID: 30902885

Abstract:

Objective:
In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models.
Design:
We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC.
Results:
The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhigh tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+ T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC.
Conclusions:
OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248559	Osteopontin from mouse			Price

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