Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment
Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacolo...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2024-12, Vol.121 (50), p.e2412157121 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Lobel, Graham P Han, Nanumi Molina Arocho, William A Silber, Michal Shoush, Jason Noji, Michael C To, Tsun Ki Jerrick Zhai, Li Lesner, Nicholas P Simon, M Celeste Haldar, Malay |
| description | Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses. |
| doi_str_mv | 10.1073/pnas.2412157121 |
| format | Article |
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How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2412157121</identifier><identifier>PMID: 39625974</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animal models ; Animals ; Antagonists ; Antigen presentation ; Cell culture ; Cell Proliferation ; Cell survival ; Dendritic cells ; Dendritic Cells - immunology ; Dendritic Cells - metabolism ; Glutamine ; Glutamine - metabolism ; Immune system ; Mice ; Mice, Inbred C57BL ; Rapamycin ; Signal Transduction ; Soft tissues ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Tumor cells ; Tumor microenvironment ; Tumor Microenvironment - immunology ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2024-12, Vol.121 (50), p.e2412157121</ispartof><rights>Copyright National Academy of Sciences Dec 10, 2024</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c209t-e64b9dda3839577d78d92659a21895940397dc2f9e5f4f86415b22aa4db49bc23</cites><orcidid>0000-0002-6996-5367</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39625974$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lobel, Graham P</creatorcontrib><creatorcontrib>Han, Nanumi</creatorcontrib><creatorcontrib>Molina Arocho, William A</creatorcontrib><creatorcontrib>Silber, Michal</creatorcontrib><creatorcontrib>Shoush, Jason</creatorcontrib><creatorcontrib>Noji, Michael C</creatorcontrib><creatorcontrib>To, Tsun Ki Jerrick</creatorcontrib><creatorcontrib>Zhai, Li</creatorcontrib><creatorcontrib>Lesner, Nicholas P</creatorcontrib><creatorcontrib>Simon, M Celeste</creatorcontrib><creatorcontrib>Haldar, Malay</creatorcontrib><title>Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antagonists</subject><subject>Antigen presentation</subject><subject>Cell culture</subject><subject>Cell Proliferation</subject><subject>Cell survival</subject><subject>Dendritic cells</subject><subject>Dendritic Cells - immunology</subject><subject>Dendritic Cells - metabolism</subject><subject>Glutamine</subject><subject>Glutamine - metabolism</subject><subject>Immune system</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Rapamycin</subject><subject>Signal Transduction</subject><subject>Soft tissues</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Tumor cells</subject><subject>Tumor microenvironment</subject><subject>Tumor Microenvironment - immunology</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc9LHTEQx0Ox1Odrz71JwEsvq_m52TkWsVYQemnPSzbJ0sgmeU2ygjf_dPOeWsHLzGE-82GGL0JfKTmnRPGLXdTlnAnKqFStfEAbSoB2vQByhDaEMNUNgoljdFLKHSEE5EA-oWMOPZOgxAY9Xi9r1cFHh33BJvvqjV7wnDKufx0O2sfqoo7G4TTj-rBzmGKT4r2L1afYUOuiPaxh45alYB9xTDm0SfWlrA7raA-uuoZmDd7k5OK9zymGJvmMPs56Ke7LS9-iPz-ufl_-7G5_Xd9cfr_tDCNQO9eLCazVfOAglbJqsMB6CZrRASQIwkFZw2Zwchbz0AsqJ8a0FnYSMBnGt-jbs3eX07_VlToGX_YX6-jSWkZOBQEm-mbaorN36F1ac_v1QEnGQFHeqItnqv1TSnbzuMs-6PwwUjLuwxn34Yxv4bSN0xfvOgVn__OvafAnElmMCg</recordid><startdate>20241210</startdate><enddate>20241210</enddate><creator>Lobel, Graham P</creator><creator>Han, Nanumi</creator><creator>Molina Arocho, William A</creator><creator>Silber, Michal</creator><creator>Shoush, Jason</creator><creator>Noji, Michael C</creator><creator>To, Tsun Ki Jerrick</creator><creator>Zhai, Li</creator><creator>Lesner, Nicholas P</creator><creator>Simon, M Celeste</creator><creator>Haldar, Malay</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-6996-5367</orcidid></search><sort><creationdate>20241210</creationdate><title>Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment</title><author>Lobel, Graham P ; 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How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. 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| subjects | Animal models Animals Antagonists Antigen presentation Cell culture Cell Proliferation Cell survival Dendritic cells Dendritic Cells - immunology Dendritic Cells - metabolism Glutamine Glutamine - metabolism Immune system Mice Mice, Inbred C57BL Rapamycin Signal Transduction Soft tissues TOR protein TOR Serine-Threonine Kinases - metabolism Tumor cells Tumor microenvironment Tumor Microenvironment - immunology Tumors |
| title | Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment |
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