Targeting Atherogenic T-cells As A Novel Therapeutic In Reducing Atherosclerosis In Humans

Background:Atherosclerosis is a systematic inflammatory disorder that leads to chronic non-resolved inflammation and pathogenesis of atherosclerotic plaques.Its immunotherapy has been promised by the CANTOS trial that targets innate immune response despite its modest efficacy.Whether targeting adaptive T-cell immunity is effective still remain conflicting and elusive.Specifically,plaque-specific complex immune compositions,their detailed functionalities and inter-cellular dynamics,T-cell receptor(TCR)repertoire,and TCR-based T-cell lineage development in plaques are still unclear,impeding the identification of clinically effective and druggable targets on immune cells for regressing atherosclerotic plaques.Thus,to identify more treatable immune targets is intriguing and necessary but requires a deep understanding of atherogenesis-associated immune alterations.Methods:We thereby delineated and exploited the comprehensive multi-omics singlecell immune atlas of human atherosclerosis by single-cell CyTOF and simultaneous scRNA-seq and scTCR-seq to characterize atherosclerosis-driven immune remodeling,especially on adaptive T-cell dynamics.Results:Unprecedentedly,we reveal that in human plaque-derived PD-1+ T cells are activated and pro-inflammatory due to PD-L1 deficiency and that they directionally differentiate toward locally long-lived LMNA+ effector memory T(TEM)cells to maintain the local unresolved chronic inflammation.We thereby developing a novel therapeutic approach to target and suppress these atherogenic PD-1+ T cells by exploiting the antiPD-1 mAbs capturing ability of myeloid-cell expressed FcγRI and using this surfaceimmobilized anti-PD-1 mAbs as pseudo-PD-1’s ligands to suppress the activation of these atherogenic PD-1+T cells.We further validate ex vivo that such approach can significantly reduce the inflammatory cytokine release from both PD-1+T cells and plaque-derived immune cells.Intriguingly,this is further supported by in vivo observation of significant shrinkages of atherosclerotic plaques with high occurring frequency in tumor patient cohort who were treated with anti-PD-1 mAbs.Thus,our work opens a door for T-cell based immunotherapy to effectively reverse human atherosclerosis.