Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies

Kuchuk, O., Tuccitto, A., Citterio, D., Huber, V., Camisaschi, C., Milione, M., et al. (2018). pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma. ONCOIMMUNOLOGY, 7(7) [10.1080/2162402X.2018.1445452].

pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma

Citterio, Davide;Vergani, Barbara;Villa, Antonello;
2018

Abstract

Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies
Articolo in rivista - Articolo scientifico
hepatocellular carcinoma; immunosuppressive cells; pH regulatory molecules; therapy; tumor microenvironment; Immunology and Allergy; Immunology; Oncology
English
2018
7
7
1445452
none
Kuchuk, O., Tuccitto, A., Citterio, D., Huber, V., Camisaschi, C., Milione, M., et al. (2018). pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma. ONCOIMMUNOLOGY, 7(7) [10.1080/2162402X.2018.1445452].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/196415
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