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

• 成果类型: Article
• 署名作者: Lobel, Graham P.; Han, Nanumi; Arocho, William A. Molina; Silber, Michal; Shoush, Jason; Noji, Michael C.; To, Tsun Ki Jerrick; Zhai, Li; Lesner, Nicholas P.; Simon, M. Celeste; Haldar, Malay
• 署名单位: University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11307
• DOI: 10.1073/pnas.2412157121
• 发表日期: 2024-12-10
• 关键词: inhibitor cb-839; mtorc1; lung; progenitors; metabolism; expression; synergizes; responses; delivery; don

摘要

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.