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

T 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. [Display omitted] •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 cells Dermatology; Immunology