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Volume 23
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Article

Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma

by
Elisa F. Brandt
1,
Maike Baues
2,
Theresa H. Wirtz
1,
Jan-Niklas May
2,
Petra Fischer
1,
Anika Beckers
1,
Björn-Carsten Schüre
2,
Hacer Sahin
1,
Christian Trautwein
1,3,
Twan Lammers
2 and
Marie-Luise Berres
1,3,*
1
Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany
2
Institute for Experimental Molecular Imaging, University Hospital RWTH Aachen, 52074 Aachen, Germany
3
Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), 52074 Aachen, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(15), 8112; https://doi.org/10.3390/ijms23158112
Submission received: 25 May 2022 / Revised: 5 July 2022 / Accepted: 9 July 2022 / Published: 23 July 2022
(This article belongs to the Special Issue Gut and the Liver in Health and Disease)
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Abstract

Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping the tumor microenvironment. C57BL/6J wild type (WT) and Cxcl10 knockout mice (Cxcl10−/−) were treated with diethylnitrosamine (DEN) and tetrachloromethane (CCl4) to induce fibrosis-associated HCCs. Cxcl10 deficiency attenuated hepatocarcinogenesis by decreasing tumor cell proliferation as well as tumor vascularization and modulated tumor-associated extracellular matrix composition. Furthermore, the genetic inactivation of Cxcl10 mediated an alteration of the tumor-associated immune response and modified chemokine/chemokine receptor networks. The DEN/CCl4-treated Cxcl10−/− mice presented with a pro-inflammatory tumor microenvironment and an accumulation of anti-tumoral immune cells in the tissue. The most striking alteration in the Cxcl10−/− tumor immune microenvironment was a vast accumulation of anti-tumoral T cells in the invasive tumor margin. In summary, our results demonstrate that CXCL10 exerts a non-redundant impact on several hallmarks of the tumor microenvironment and especially modulates the infiltration of anti-tumorigenic immune cells in HCC. In the era of microenvironment-targeted HCC therapies, interfering with CXCL10 defines a novel asset for further improvement of therapeutic strategies.
Keywords: CXCL10; hepatocellular carcinoma; tumor microenvironment; tumor-associated immune response; tumor cell proliferation; angiogenesis; chemokine/chemokine receptor network CXCL10; hepatocellular carcinoma; tumor microenvironment; tumor-associated immune response; tumor cell proliferation; angiogenesis; chemokine/chemokine receptor network

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MDPI and ACS Style

Brandt, E.F.; Baues, M.; Wirtz, T.H.; May, J.-N.; Fischer, P.; Beckers, A.; Schüre, B.-C.; Sahin, H.; Trautwein, C.; Lammers, T.; et al. Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma. Int. J. Mol. Sci. 2022, 23, 8112. https://doi.org/10.3390/ijms23158112

AMA Style

Brandt EF, Baues M, Wirtz TH, May J-N, Fischer P, Beckers A, Schüre B-C, Sahin H, Trautwein C, Lammers T, et al. Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2022; 23(15):8112. https://doi.org/10.3390/ijms23158112

Chicago/Turabian Style

Brandt, Elisa F., Maike Baues, Theresa H. Wirtz, Jan-Niklas May, Petra Fischer, Anika Beckers, Björn-Carsten Schüre, Hacer Sahin, Christian Trautwein, Twan Lammers, and et al. 2022. "Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma" International Journal of Molecular Sciences 23, no. 15: 8112. https://doi.org/10.3390/ijms23158112

APA Style

Brandt, E. F., Baues, M., Wirtz, T. H., May, J.-N., Fischer, P., Beckers, A., Schüre, B.-C., Sahin, H., Trautwein, C., Lammers, T., & Berres, M.-L. (2022). Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma. International Journal of Molecular Sciences, 23(15), 8112. https://doi.org/10.3390/ijms23158112

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