PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell Carcinoma
The immune checkpoint programmed death-ligand 1 (PD-L1) is expressed on the cell surface of tumor cells and is key for maintaining an immunosuppressive microenvironment through its interaction with the programmed death 1 (PD-1). Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic cancer...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.858379/full |
| _version_ | 1828365605256822784 |
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| author | Mamatha Garige Susmita Ghosh Alexis Norris Guangyuan Li Sarah Poncet Chao-Kai Chou Wells W. Wu Rong-Fong Shen Carole Sourbier |
| author_facet | Mamatha Garige Susmita Ghosh Alexis Norris Guangyuan Li Sarah Poncet Chao-Kai Chou Wells W. Wu Rong-Fong Shen Carole Sourbier |
| author_sort | Mamatha Garige |
| collection | DOAJ |
| description | The immune checkpoint programmed death-ligand 1 (PD-L1) is expressed on the cell surface of tumor cells and is key for maintaining an immunosuppressive microenvironment through its interaction with the programmed death 1 (PD-1). Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic cancer characterized by an aberrant aerobic glycolytic metabolism and is known to overexpress PD-L1. Multiple immunotherapies have been approved for the treatment of ccRCC, including cytokines and immune checkpoint inhibitors. Recently the intrinsic role of PD-L1 and interferon gamma (IFNγ) signaling have been studied in several types of tumor cells, yet it remains unclear how they affect the metabolism and signaling pathways of ccRCC. Using metabolomics, metabolic assays and RNAseq, we showed that IFNγ enhanced aerobic glycolysis and tryptophan metabolism in ccRCC cells in vitro and induced the transcriptional expression of signaling pathways related to inflammation, cell proliferation and cellular energetics. These metabolic and transcriptional effects were partially reversed following transient PD-L1 silencing. Aerobic glycolysis, as well as signaling pathways related to inflammation, were not induced by IFNγ when PD-L1 was silenced, however, tryptophan metabolism and activation of Jak2 and STAT1 were maintained. Our data demonstrate that PD-L1 expression is required to mediate some of IFNγ’s effect in ccRCC cells and highlight the importance of PD-L1 signaling in regulating the metabolism of ccRCC cells in response to inflammatory signals. |
| first_indexed | 2024-04-14T05:34:17Z |
| format | Article |
| id | doaj.art-f478bab173b34a1bb08f1f2d8c0707c4 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T05:34:17Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f478bab173b34a1bb08f1f2d8c0707c42022-12-22T02:09:43ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-05-011210.3389/fonc.2022.858379858379PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell CarcinomaMamatha Garige0Susmita Ghosh1Alexis Norris2Guangyuan Li3Sarah Poncet4Chao-Kai Chou5Wells W. Wu6Rong-Fong Shen7Carole Sourbier8Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Animal Bioengineering and Cellular Therapies, Office of New Animal Drug Evaluation, Center for Veterinary Medicine, United States Food and Drug Administration, Rockville, MD, United StatesDivision of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesFacility for Biotechnology Resources, Center for Biologicals Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesFacility for Biotechnology Resources, Center for Biologicals Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesFacility for Biotechnology Resources, Center for Biologicals Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesThe immune checkpoint programmed death-ligand 1 (PD-L1) is expressed on the cell surface of tumor cells and is key for maintaining an immunosuppressive microenvironment through its interaction with the programmed death 1 (PD-1). Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic cancer characterized by an aberrant aerobic glycolytic metabolism and is known to overexpress PD-L1. Multiple immunotherapies have been approved for the treatment of ccRCC, including cytokines and immune checkpoint inhibitors. Recently the intrinsic role of PD-L1 and interferon gamma (IFNγ) signaling have been studied in several types of tumor cells, yet it remains unclear how they affect the metabolism and signaling pathways of ccRCC. Using metabolomics, metabolic assays and RNAseq, we showed that IFNγ enhanced aerobic glycolysis and tryptophan metabolism in ccRCC cells in vitro and induced the transcriptional expression of signaling pathways related to inflammation, cell proliferation and cellular energetics. These metabolic and transcriptional effects were partially reversed following transient PD-L1 silencing. Aerobic glycolysis, as well as signaling pathways related to inflammation, were not induced by IFNγ when PD-L1 was silenced, however, tryptophan metabolism and activation of Jak2 and STAT1 were maintained. Our data demonstrate that PD-L1 expression is required to mediate some of IFNγ’s effect in ccRCC cells and highlight the importance of PD-L1 signaling in regulating the metabolism of ccRCC cells in response to inflammatory signals.https://www.frontiersin.org/articles/10.3389/fonc.2022.858379/fullPD-L1 (B7-H1CD274)clear cell renal cell carcinoma (ccRCC)interferon gammametabolismtryptophan |
| spellingShingle | Mamatha Garige Susmita Ghosh Alexis Norris Guangyuan Li Sarah Poncet Chao-Kai Chou Wells W. Wu Rong-Fong Shen Carole Sourbier PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell Carcinoma Frontiers in Oncology PD-L1 (B7-H1 CD274) clear cell renal cell carcinoma (ccRCC) interferon gamma metabolism tryptophan |
| title | PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell Carcinoma |
| title_full | PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell Carcinoma |
| title_fullStr | PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell Carcinoma |
| title_full_unstemmed | PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell Carcinoma |
| title_short | PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell Carcinoma |
| title_sort | pd l1 mediates ifnγ regulation of glucose but not of tryptophan metabolism in clear cell renal cell carcinoma |
| topic | PD-L1 (B7-H1 CD274) clear cell renal cell carcinoma (ccRCC) interferon gamma metabolism tryptophan |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.858379/full |
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