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

Chattopadhyay, A and Jagdish, S and Karhale, AK and Ramteke, NS and Zaib, A and Nandi, D (2023) IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy. In: Frontiers in Immunology, 14 .

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Official URL: https://doi.org/10.3389/fimmu.2023.1282653


Introduction: Interferon-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. Methods: In this study, the response of various tumor cell lines to IFN-γ was studied in vitro. Results: IFN-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. Discussion: Clinical 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. Copyright © 2023 Chattopadhyay, Jagdish, Karhale, Ramteke, Zaib and Nandi.

Item Type: Journal Article
Publication: Frontiers in Immunology
Publisher: Frontiers Media SA
Additional Information: The copyright for this article belongs to authors.
Keywords: gamma interferon; lactate dehydrogenase; lactic acid; nitric oxide; reactive oxygen metabolite; lactic acid; nitric oxide, apoptosis; Article; B16-F10 cell line; cancer immunotherapy; cell cycle arrest; cell growth; colorimetry; CT26 cell line; extracellular acidification rate; flow cytometry; glucose transport; glycolysis; human; human cell; liver cell carcinoma; microtiter plate assay; mitochondrial membrane potential; mitochondrion; protein expression; RAW 264.7 cell line; real time polymerase chain reaction; renal cell carcinoma; RenCa cell line; RNA isolation; seahorse; tumor growth; tumor microenvironment; glycolysis; hypoxia; metabolism; neoplasm; tumor cell line, Cell Line, Tumor; Glycolysis; Humans; Hypoxia; Interferon-gamma; Lactic Acid; Neoplasms; Nitric Oxide; Reactive Oxygen Species
Department/Centre: Division of Biological Sciences > Biochemistry
Date Deposited: 25 Apr 2024 07:11
Last Modified: 25 Apr 2024 07:11
URI: https://eprints.iisc.ac.in/id/eprint/84338

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