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

Oncoimmunology. 2018 Mar 26;7(7):e1445452. doi: 10.1080/2162402X.2018.1445452. eCollection 2018.


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.

Keywords: hepatocellular carcinoma; immunosuppressive cells; pH regulatory molecules; therapy; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

Grants and funding

Associazione Italiana Ricerca sul Cancro ID: CC IG-15192, Italian Ministry of Health ID: 52/RF-2010-2312620, Associazione Italiana Ricerca sul Cancro ID: LR IG-14285. Fellowship provided by Prometeo Association.