IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy
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 t...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-10-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1282653/full |
| _version_ | 1797647654419693568 |
|---|---|
| author | Avik Chattopadhyay Sirisha Jagdish Aagosh Kishor Karhale Nikita S. Ramteke Arsha Zaib Dipankar Nandi |
| author_facet | Avik Chattopadhyay Sirisha Jagdish Aagosh Kishor Karhale Nikita S. Ramteke Arsha Zaib Dipankar Nandi |
| author_sort | Avik Chattopadhyay |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T15:20:38Z |
| format | Article |
| id | doaj.art-ebcfdba463ee4da2be33dd25be8a5e1d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T15:20:38Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ebcfdba463ee4da2be33dd25be8a5e1d2023-10-28T21:30:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12826531282653IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapyAvik ChattopadhyaySirisha JagdishAagosh Kishor KarhaleNikita S. RamtekeArsha ZaibDipankar NandiIntroductionInterferon-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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1282653/fullinterferon-gammanitric oxidelactateHIF-1 alphatumor |
| spellingShingle | Avik Chattopadhyay Sirisha Jagdish Aagosh Kishor Karhale Nikita S. Ramteke Arsha Zaib Dipankar Nandi IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy Frontiers in Immunology interferon-gamma nitric oxide lactate HIF-1 alpha tumor |
| title | IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy |
| title_full | IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy |
| title_fullStr | IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy |
| title_full_unstemmed | IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy |
| title_short | IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy |
| title_sort | ifn γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide dependent manner implications for cancer immunotherapy |
| topic | interferon-gamma nitric oxide lactate HIF-1 alpha tumor |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1282653/full |
| work_keys_str_mv | AT avikchattopadhyay ifnglowerstumorgrowthbyincreasingglycolysisandlactateproductioninanitricoxidedependentmannerimplicationsforcancerimmunotherapy AT sirishajagdish ifnglowerstumorgrowthbyincreasingglycolysisandlactateproductioninanitricoxidedependentmannerimplicationsforcancerimmunotherapy AT aagoshkishorkarhale ifnglowerstumorgrowthbyincreasingglycolysisandlactateproductioninanitricoxidedependentmannerimplicationsforcancerimmunotherapy AT nikitasramteke ifnglowerstumorgrowthbyincreasingglycolysisandlactateproductioninanitricoxidedependentmannerimplicationsforcancerimmunotherapy AT arshazaib ifnglowerstumorgrowthbyincreasingglycolysisandlactateproductioninanitricoxidedependentmannerimplicationsforcancerimmunotherapy AT dipankarnandi ifnglowerstumorgrowthbyincreasingglycolysisandlactateproductioninanitricoxidedependentmannerimplicationsforcancerimmunotherapy |