Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer
Abstract Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prod...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-09-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202105885 |
| _version_ | 1797817511066992640 |
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| author | Mofei Huang Donghai Xiong Jing Pan Qi Zhang Shizuko Sei Robert H. Shoemaker Ronald A. Lubet Luis M. Montuenga Yian Wang Barbara S. Slusher Ming You |
| author_facet | Mofei Huang Donghai Xiong Jing Pan Qi Zhang Shizuko Sei Robert H. Shoemaker Ronald A. Lubet Luis M. Montuenga Yian Wang Barbara S. Slusher Ming You |
| author_sort | Mofei Huang |
| collection | DOAJ |
| description | Abstract Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR‐driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single‐cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8+ T cell and CD4+ Th1 cell infiltration, while EVax elicits robust Th1 cell‐mediated immune responses and protects mice against EGFRL858R mutation‐driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic‐ and granulocytic‐myeloid‐derived suppressor cells, regulatory T cells, and pro‐tumor CD4+ Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory‐like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR‐driven lung tumorigenesis and promotes an adaptive T cell‐mediated tumor‐specific immune response that enhances the efficacy of EVax. |
| first_indexed | 2024-03-13T08:54:32Z |
| format | Article |
| id | doaj.art-9cefa07a6ed841a685c42978f76082d2 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-13T08:54:32Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-9cefa07a6ed841a685c42978f76082d22023-05-29T04:01:40ZengWileyAdvanced Science2198-38442022-09-01926n/an/a10.1002/advs.202105885Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung CancerMofei Huang0Donghai Xiong1Jing Pan2Qi Zhang3Shizuko Sei4Robert H. Shoemaker5Ronald A. Lubet6Luis M. Montuenga7Yian Wang8Barbara S. Slusher9Ming You10Center for Cancer Prevention Houston Methodist Cancer Center Houston Methodist Research Institute Houston TX 77030 USACenter for Cancer Prevention Houston Methodist Cancer Center Houston Methodist Research Institute Houston TX 77030 USACenter for Cancer Prevention Houston Methodist Cancer Center Houston Methodist Research Institute Houston TX 77030 USACenter for Cancer Prevention Houston Methodist Cancer Center Houston Methodist Research Institute Houston TX 77030 USAChemopreventive Agent Development Research Group Division of Cancer Prevention National Cancer Institute Bethesda MD 20850 USAChemopreventive Agent Development Research Group Division of Cancer Prevention National Cancer Institute Bethesda MD 20850 USAChemopreventive Agent Development Research Group Division of Cancer Prevention National Cancer Institute Bethesda MD 20850 USAProgram in Solid Tumors and Biomarkers Center for Applied Medical Research (CIMA) University of Navarra Pamplona 31009 SpainCenter for Cancer Prevention Houston Methodist Cancer Center Houston Methodist Research Institute Houston TX 77030 USAJohns Hopkins Drug Discovery Johns Hopkins University School of Medicine Baltimore MD 21205 USACenter for Cancer Prevention Houston Methodist Cancer Center Houston Methodist Research Institute Houston TX 77030 USAAbstract Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR‐driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single‐cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8+ T cell and CD4+ Th1 cell infiltration, while EVax elicits robust Th1 cell‐mediated immune responses and protects mice against EGFRL858R mutation‐driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic‐ and granulocytic‐myeloid‐derived suppressor cells, regulatory T cells, and pro‐tumor CD4+ Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory‐like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR‐driven lung tumorigenesis and promotes an adaptive T cell‐mediated tumor‐specific immune response that enhances the efficacy of EVax.https://doi.org/10.1002/advs.202105885epidermal growth factor receptor vaccinesglutamine metabolismJHU‐083lung tumorigenesistumor immune microenvironment |
| spellingShingle | Mofei Huang Donghai Xiong Jing Pan Qi Zhang Shizuko Sei Robert H. Shoemaker Ronald A. Lubet Luis M. Montuenga Yian Wang Barbara S. Slusher Ming You Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer Advanced Science epidermal growth factor receptor vaccines glutamine metabolism JHU‐083 lung tumorigenesis tumor immune microenvironment |
| title | Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer |
| title_full | Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer |
| title_fullStr | Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer |
| title_full_unstemmed | Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer |
| title_short | Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer |
| title_sort | targeting glutamine metabolism to enhance immunoprevention of egfr driven lung cancer |
| topic | epidermal growth factor receptor vaccines glutamine metabolism JHU‐083 lung tumorigenesis tumor immune microenvironment |
| url | https://doi.org/10.1002/advs.202105885 |
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