PH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma. (3rd July 2018)

• Record Type: Journal Article
• 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
• Is Part Of: Oncoimmunology. Volume 7:Number 7(2018)
• Publication Date: 2018-07-03
• Subjects: hepatocellular carcinoma -- pH regulatory molecules -- therapy -- tumor microenvironment -- immunosuppressive cells; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2018.1445452
• Languages: English
• ISSNs: 2162-402X

Abstract

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.