018 Imiquimod perturbs amino acid metabolism in human CD8+ T cells

      Imiquimod (IMQ), a TLR7 agonist, is a standard local treatment for non-melanoma skin cancers (NMSC). IMQ triggers inflammation, ultimately resulting in immunological tumor destruction. Albeit IMQ promotes the recruitment of effector T (TE) cells, IMQ triggers anergy in CD4+ T cells. Meanwhile, how IMQ affects human CD8+ TE cells, pivotal to immunological cancer control, remains unclear. To address this, we studied CD8+ TE cell lines from NMSC and circulating, skin-homing CLA+CD8+ TE cells. In both models, IMQ-treated TE cells showed significantly reduced proliferation and IFN-γ production. Because metabolism fundamentally underlies the function of T cells, we hypothesized that metabolic changes underlie the suppressive effects of IMQ on TE cells. Along this idea, we found that IMQ-treated TE cells have reduced mTOR activity. To gain broader insight into metabolic adaptations of IMQ-treated T cells, we performed proteomics, revealing dysregulation of amino acid (AA) transporters, especially the SLC1A5 transporter in IMQ-treated CD8+ TE cells. Meanwhile, IMQ reduced intracellular levels of AA transported by SLC1A5, including glutamine, asparagine, aspartic acid. Consistent with a known supportive role of several AA, including glutamine and asparagine, in TE responses, adding these AA to IMQ-treated TE cells restored effector functions. Our finding that SLC1A5-dependent AA rescue IMQ-induced hypo-responsiveness of CD8+ TE cells provides a rational for studying if exogenous AA can improve effectiveness of IMQ-based destructive NMSC therapies.