Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells
Abstract Colorectal cancer (CRC) cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro‐tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. Colorectal tumors with high glutaminase (GLS) expre...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202310308 |
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| author | Tao Yu Kevin Van der Jeught Haiqi Zhu Zhuolong Zhou Samantha Sharma Sheng Liu Haniyeh Eyvani Ka Man So Naresh Singh Jia Wang George E. Sandusky Yunlong Liu Mateusz Opyrchal Sha Cao Jun Wan Chi Zhang Xinna Zhang |
| author_facet | Tao Yu Kevin Van der Jeught Haiqi Zhu Zhuolong Zhou Samantha Sharma Sheng Liu Haniyeh Eyvani Ka Man So Naresh Singh Jia Wang George E. Sandusky Yunlong Liu Mateusz Opyrchal Sha Cao Jun Wan Chi Zhang Xinna Zhang |
| author_sort | Tao Yu |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC) cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro‐tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. Colorectal tumors with high glutaminase (GLS) expression exhibited reduced T cell infiltration and cytotoxicity, leading to poor clinical outcomes. However, depletion of GLS in CRC cells has minimal effect on tumor growth in immunocompromised mice. By contrast, remarkable inhibition of tumor growth is observed in immunocompetent mice when GLS is knocked down. It is found that GLS knockdown in CRC cells enhanced the cytotoxicity of tumor‐specific T cells. Furthermore, the single‐cell flux estimation analysis (scFEA) of glutamine metabolism revealed that glutamate‐to‐glutathione (Glu‐GSH) flux, downstream of GLS, rather than Glu‐to‐2‐oxoglutarate flux plays a key role in regulating the immune response of CRC cells in the tumor. Mechanistically, inhibition of the Glu‐GSH flux activated reactive oxygen species (ROS)‐related signaling pathways in tumor cells, thereby increasing the tumor immunogenicity by promoting the activity of the immunoproteasome. The combinatorial therapy of Glu‐GSH flux inhibitor and anti‐PD‐1 antibody exhibited a superior tumor growth inhibitory effect compared to either monotherapy. Taken together, the study provides the first evidence pointing to Glu‐GSH flux as a potential therapeutic target for CRC immunotherapy. |
| format | Article |
| id | doaj-art-bc432c7ef9ea4552957683862fc8fdd1 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-bc432c7ef9ea4552957683862fc8fdd12025-01-09T11:44:45ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202310308Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer CellsTao Yu0Kevin Van der Jeught1Haiqi Zhu2Zhuolong Zhou3Samantha Sharma4Sheng Liu5Haniyeh Eyvani6Ka Man So7Naresh Singh8Jia Wang9George E. Sandusky10Yunlong Liu11Mateusz Opyrchal12Sha Cao13Jun Wan14Chi Zhang15Xinna Zhang16Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USACenter for Computational Biology and Bioinformatics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USACenter for Computational Biology and Bioinformatics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USAMelvin and Bren Simon Comprehensive Cancer Center Indiana University School of Medicine Indianapolis IN 46202 USAMelvin and Bren Simon Comprehensive Cancer Center Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USADepartment of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USAAbstract Colorectal cancer (CRC) cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro‐tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. Colorectal tumors with high glutaminase (GLS) expression exhibited reduced T cell infiltration and cytotoxicity, leading to poor clinical outcomes. However, depletion of GLS in CRC cells has minimal effect on tumor growth in immunocompromised mice. By contrast, remarkable inhibition of tumor growth is observed in immunocompetent mice when GLS is knocked down. It is found that GLS knockdown in CRC cells enhanced the cytotoxicity of tumor‐specific T cells. Furthermore, the single‐cell flux estimation analysis (scFEA) of glutamine metabolism revealed that glutamate‐to‐glutathione (Glu‐GSH) flux, downstream of GLS, rather than Glu‐to‐2‐oxoglutarate flux plays a key role in regulating the immune response of CRC cells in the tumor. Mechanistically, inhibition of the Glu‐GSH flux activated reactive oxygen species (ROS)‐related signaling pathways in tumor cells, thereby increasing the tumor immunogenicity by promoting the activity of the immunoproteasome. The combinatorial therapy of Glu‐GSH flux inhibitor and anti‐PD‐1 antibody exhibited a superior tumor growth inhibitory effect compared to either monotherapy. Taken together, the study provides the first evidence pointing to Glu‐GSH flux as a potential therapeutic target for CRC immunotherapy.https://doi.org/10.1002/advs.202310308colorectal cancerglutamine metabolismimmune checkpoint blockadeimmunoproteasomeMHC‐I antigen presentationsingle‐cell flux estimation analysis |
| spellingShingle | Tao Yu Kevin Van der Jeught Haiqi Zhu Zhuolong Zhou Samantha Sharma Sheng Liu Haniyeh Eyvani Ka Man So Naresh Singh Jia Wang George E. Sandusky Yunlong Liu Mateusz Opyrchal Sha Cao Jun Wan Chi Zhang Xinna Zhang Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells Advanced Science colorectal cancer glutamine metabolism immune checkpoint blockade immunoproteasome MHC‐I antigen presentation single‐cell flux estimation analysis |
| title | Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells |
| title_full | Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells |
| title_fullStr | Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells |
| title_full_unstemmed | Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells |
| title_short | Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells |
| title_sort | inhibition of glutamate to glutathione flux promotes tumor antigen presentation in colorectal cancer cells |
| topic | colorectal cancer glutamine metabolism immune checkpoint blockade immunoproteasome MHC‐I antigen presentation single‐cell flux estimation analysis |
| url | https://doi.org/10.1002/advs.202310308 |
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