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

• Published in: Oncoimmunology Vol. 7; no. 7; p. e1445452
• Main Authors: Kuchuk, Olga, Tuccitto, Alessandra, Citterio, Davide, Huber, Veronica, Camisaschi, Chiara, Milione, Massimo, Vergani, Barbara, Villa, Antonello, Alison, Malcolm Ronald, Carradori, Simone, Supuran, Claudiu T, Rivoltini, Licia, Castelli, Chiara, Mazzaferro, Vincenzo
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 03.07.2018; Taylor & Francis Group
• Subjects: hepatocellular carcinoma; immunosuppressive cells; Original Research; pH regulatory molecules; therapy; tumor microenvironment; immunosuppressive cells; pH regulatory molecules; tumor microenvironment; therapy; hepatocellular carcinoma
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2018.1445452

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.