Glutamine is Critical for the Maintenance of Type 1 Conventional Dendritic Cells in Normal Tissue and the Tumor Microenvironment

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2024 Dec 3

PMID 39625974

Authors

Graham P Lobel

Nanumi Han

William A Molina Arocho

Michal Silber

Jason Shoush

Michael C Noji

Tsun Ki Jerrick To

Li Zhai

Nicholas P Lesner

M Celeste Simon

Malay Haldar

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.

Lobel G, Han N, Molina Arocho W, Silber M, Shoush J, Noji M Proc Natl Acad Sci U S A. 2024; 121(50):e2412157121.

PMID: 39625974 PMC: 11648871. DOI: 10.1073/pnas.2412157121.

References

Edwards D, Ngwa V, Raybuck A, Wang S, Hwang Y, Kim L . Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest. 2020; 131(4. PMC: 7880417. DOI: 10.1172/JCI140100. View

DeBerardinis R, Cheng T . Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2009; 29(3):313-24. PMC: 2809806. DOI: 10.1038/onc.2009.358. View

Barry K, Hsu J, Broz M, Cueto F, Binnewies M, Combes A . A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat Med. 2018; 24(8):1178-1191. PMC: 6475503. DOI: 10.1038/s41591-018-0085-8. View

Lee C, Motzer R, Emamekhoo H, Matrana M, Percent I, Hsieh J . Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial. Clin Cancer Res. 2022; 28(15):3248-3255. PMC: 10202043. DOI: 10.1158/1078-0432.CCR-22-0061. View

Kirsch D, Dinulescu D, Miller J, Grimm J, Santiago P, Young N . A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat Med. 2007; 13(8):992-7. DOI: 10.1038/nm1602. View

Devalaraja S, To T, Folkert I, Natesan R, Alam M, Li M . Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression. Cell. 2020; 180(6):1098-1114.e16. PMC: 7194250. DOI: 10.1016/j.cell.2020.02.042. View

Araujo L, Khim P, Mkhikian H, Mortales C, Demetriou M . Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. Elife. 2017; 6. PMC: 5257256. DOI: 10.7554/eLife.21330. View

Rais R, Jancarik A, Tenora L, Nedelcovych M, Alt J, Englert J . Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma. J Med Chem. 2016; 59(18):8621-33. DOI: 10.1021/acs.jmedchem.6b01069. View

Nakaya M, Xiao Y, Zhou X, Chang J, Chang M, Cheng X . Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 2014; 40(5):692-705. PMC: 4074507. DOI: 10.1016/j.immuni.2014.04.007. View

10.

Leone R, Zhao L, Englert J, Sun I, Oh M, Sun I . Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019; 366(6468):1013-1021. PMC: 7023461. DOI: 10.1126/science.aav2588. View

11.

Sugiura A, Andrejeva G, Voss K, Heintzman D, Xu X, Madden M . MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function. Immunity. 2021; 55(1):65-81.e9. PMC: 8755618. DOI: 10.1016/j.immuni.2021.10.011. View

12.

Yu Q, Tu H, Yin X, Peng C, Dou C, Yang W . Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis Inhibiting T Cell Activation and Differentiation. Front Immunol. 2022; 13:880262. PMC: 9160195. DOI: 10.3389/fimmu.2022.880262. View

13.

Biancur D, Paulo J, Malachowska B, Del Rey M, Sousa C, Wang X . Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nat Commun. 2017; 8:15965. PMC: 5500878. DOI: 10.1038/ncomms15965. View

14.

Gross M, Demo S, Dennison J, Chen L, Chernov-Rogan T, Goyal B . Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014; 13(4):890-901. DOI: 10.1158/1535-7163.MCT-13-0870. View

15.

Dang M, Mafra F, Haldar M . Isolation of myeloid cells from mouse brain tumors for single-cell RNA-seq analysis. STAR Protoc. 2021; 2(4):100957. PMC: 8605103. DOI: 10.1016/j.xpro.2021.100957. View

16.

Davidson S, Papagiannakopoulos T, Olenchock B, Heyman J, Keibler M, Luengo A . Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer. Cell Metab. 2016; 23(3):517-28. PMC: 4785096. DOI: 10.1016/j.cmet.2016.01.007. View

17.

Encarnacion-Rosado J, Sohn A, Biancur D, Lin E, Osorio-Vasquez V, Rodrick T . Targeting pancreatic cancer metabolic dependencies through glutamine antagonism. Nat Cancer. 2023; 5(1):85-99. PMC: 10824664. DOI: 10.1038/s43018-023-00647-3. View

18.

Rais R, Lemberg K, Tenora L, Arwood M, Pal A, Alt J . Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci Adv. 2022; 8(46):eabq5925. PMC: 9668306. DOI: 10.1126/sciadv.abq5925. View

19.

Johnson M, Wolf M, Madden M, Andrejeva G, Sugiura A, Contreras D . Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism. Cell. 2018; 175(7):1780-1795.e19. PMC: 6361668. DOI: 10.1016/j.cell.2018.10.001. View

20.

Kc W, Satpathy A, Rapaport A, Briseno C, Wu X, Albring J . L-Myc expression by dendritic cells is required for optimal T-cell priming. Nature. 2014; 507(7491):243-7. PMC: 3954917. DOI: 10.1038/nature12967. View