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

OncoImmunology

Malcolm Ronald Alison¹  Barbara Vergani²  Antonello Villa²  Massimo Milione³  Davide Citterio³  Vincenzo Mazzaferro³  Claudiu T Supuran⁴  Olga Kuchuk⁵  Chiara Camisaschi⁵  Alessandra Tuccitto⁵  Veronica Huber⁵  Licia Rivoltini⁵  Chiara Castelli⁵  Simone Carradori⁶ 

[1] Centre for Tumour Biology, Barts Cancer Institute;Consorzio MIA (Microscopy and Image Analysis), University of Milano-Bicocca;Fondazione IRCCS Istituto Nazionale dei Tumori;Polo Scientifico, Department of Pharmaceutical Sciences;Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori;“G. D'Annunzio” University of Chieti-Pescara;

关键词: hepatocellular carcinoma;    ph regulatory molecules;    therapy;    tumor microenvironment;    immunosuppressive cells;   

DOI  :  10.1080/2162402X.2018.1445452

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown