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

Frontiers in Immunology

Immunology

Avik Chattopadhyay¹  Dipankar Nandi¹  Sirisha Jagdish¹  Arsha Zaib¹  Aagosh Kishor Karhale¹  Nikita S. Ramteke¹ 

[1] Department of Biochemistry, Indian Institute of Science, Bangalore, India;

关键词: interferon-gamma;    nitric oxide;    lactate;    HIF-1 alpha;    tumor;   

DOI  :  10.3389/fimmu.2023.1282653

 received in 2023-08-24, accepted in 2023-10-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionInterferon-gamma (IFN-γ), 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-γ in the tumor microenvironment determine the host responses against tumors; however, several tumors employ evasive strategies by responding to low IFN-γ signaling.MethodsIn this study, the response of various tumor cell lines to IFN-γ was studied in vitro. ResultsIFN-γ-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)-1α stabilization and HIF-1α-dependent augmentation of the glycolytic flux. The IFN-γ 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-γ-activation. HIF-1α stabilization upon IFN-γ-activation led to lower cell growth of B16F10 but not CT26 cells. Importantly, the IFN-γ-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-γ 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-γ activation on heterogeneous tumor cells are discussed.

【 授权许可】

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Copyright © 2023 Chattopadhyay, Jagdish, Karhale, Ramteke, Zaib and Nandi