IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy

IntroductionInterferon-gamma (IFN-gamma), the sole member of the type-II interferon family, is well known to protect the host from infectious diseases as well as mount anti-tumor responses. The amounts of IFN-gamma in the tumor microenvironment determine the host responses against tumors; however, several tumors employ evasive strategies by responding to low IFN-gamma signaling.MethodsIn this study, the response of various tumor cell lines to IFN-gamma was studied in vitro.ResultsIFN-gamma-activation increases glycolytic flux and reduces mitochondrial function in a nitric oxide (NO)- and reactive oxygen species (ROS)-dependent manner in the H6 hepatoma tumor cell line. The higher glycolysis further fueled NO and ROS production, indicating a reciprocal regulation. These processes are accompanied by Hypoxia inducing factor (HIF)-1 alpha stabilization and HIF-1 alpha-dependent augmentation of the glycolytic flux. The IFN-gamma enhancement of lactate production also occurred in other NO-producing cell lines: RAW 264.7 monocyte/macrophage and Renca renal adenocarcinoma. However, two other tumor cell lines, CT26 colon carcinoma and B16F10 melanoma, did not produce NO and lactate upon IFN-gamma-activation. HIF-1 alpha stabilization upon IFN-gamma-activation led to lower cell growth of B16F10 but not CT26 cells. Importantly, the IFN-gamma-activation of both CT26 and B16F10 cells demonstrated significant cellular growth reduction upon metabolic rewiring by exogenous administration of potassium lactate.DiscussionClinical studies have shown the crucial roles of IFN-gamma for successful cancer immunotherapies involving checkpoint inhibitors and chimeric antigen receptor T cells. The positive implications of this study on the metabolic modulation of IFN-gamma activation on heterogeneous tumor cells are discussed.