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Glutamine promotes human CD8+ T cells and counteracts imiquimod-induced T cell hyporesponsiveness

2024; Cell Press; Volume: 27; Issue: 5 Linguagem: Inglês

10.1016/j.isci.2024.109767

2589-0042

Luisa Bopp, Maria Lopéz Martinez, Clara Schumacher, Robert Seitz, Manuel Huerta Arana, Henning Klapproth, Dominika Lukas, Ju Hee Oh, Daniela Neumayer, Jan‐Wilm Lackmann, Stefan C. Mueller, Esther von Stebut, Bent Brachvogel, Susanne Brodesser, Ramon I. Klein Geltink, Mario Fabri,

CAR-T cell therapy research

Highlights•Gln is an abundant extracellular amino acid in cutaneous human (pre)-cancer•Gln enhances IFN-γ production by human CD8+ T cells•Imiquimod perturbs CD8+ T cell AA metabolism, IFN-γ production, and proliferation•Gln is sufficient to promote IFN-γ production in imiquimod-treated CD8+ T cellsSummaryT cells protect tissues from cancer. Although investigations in mice showed that amino acids (AA) critically regulate T cell immunity, this remains poorly understood in humans. Here, we describe the AA composition of interstitial fluids in keratinocyte-derived skin cancers (KDSCs) and study the effect of AA on T cells using models of primary human cells and tissues. Gln contributed to ∼15% of interstitial AAs and promoted interferon gamma (IFN-γ), but not granzyme B (GzB) expression, in CD8+ T cells. Furthermore, the Toll-like receptor 7 agonist imiquimod (IMQ), a common treatment for KDSCs, down-regulated the metabolic gatekeepers c-MYC and mTORC1, as well as the AA transporter ASCT2 and intracellular Gln, Asn, Ala, and Asp in T cells. Reduced proliferation and IFN-γ expression, yet increased GzB, paralleled IMQ effects on AA. Finally, Gln was sufficient to promote IFN-γ-production in IMQ-treated T cells. Our findings indicate that Gln metabolism can be harnessed for treating KDSCs.Graphical abstract