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 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.
Authors
- Nicholas P. Lesner (ORCID: https://orcid.org/0000-0001-9734-8828)
- William A. Molina Arocho (ORCID: https://orcid.org/0000-0002-5864-1383)
- Li Zhai (ORCID: https://orcid.org/0000-0002-9844-1554)
- Graham P. Lobel (ORCID: https://orcid.org/0000-0002-9166-2979)
- Jason Shoush (ORCID: https://orcid.org/0000-0002-4464-1657)
- Tsun Ki Jerrick To
- Michael Noji (ORCID: https://orcid.org/0000-0002-6996-5367)
- Nanumi Han (ORCID: https://orcid.org/0000-0001-9524-1808)
- M. Celeste Simon (ORCID: https://orcid.org/0000-0001-7213-9499)
- Michal Silber (ORCID: https://orcid.org/0000-0003-4884-3130)
- Malay Haldar (ORCID: https://orcid.org/0000-0003-4195-6060)
Institutions
- Cancer Research Institute (US)
- UPMC Hillman Cancer Center (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1073/pnas.2412157121
- Citations
- 6
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 1.44
Funders
- Cancer Research Institute
- Damon Runyon Cancer Research Foundation
- Children's Hospital of Philadelphia
- University of Pennsylvania
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- NHLBI Division of Intramural Research
- Division of Diabetes, Endocrinology, and Metabolic Diseases