期刊
ONCOIMMUNOLOGY
卷 7, 期 7, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2018.1445452
关键词
hepatocellular carcinoma; pH regulatory molecules; therapy; tumor microenvironment; immunosuppressive cells
资金
- Associazione Italiana Ricerca sul Cancro [CC IG-15192, LR IG-14285]
- Italian Ministry of Health [52/RF-2010-2312620]
- Prometeo Association
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.
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