Modulation of co-signaling for improved ex vivo human antigen-specific T cells generation for immunotherapy

      T cell-based immunotherapies are a promising approach to treat cancers and infections. However, various obstacles limit effective T-cell generation ex vivo, including terminal T-cell effector differentiation, exhaustion and eventually cell loss. The acquisition of dysfunctional features and terminal differentiation predicts for lack of proliferation and persistence following adoptive transfer, leading to poor efficacy. Co-inhibitory or “immune checkpoint” receptors play important role in T cell differentiation and fate. Our data showed that following ex vivo human T-cell stimulation with peptide loaded dendritic cells, a high fraction express the co-inhibitory receptors PD-1 and TIM3, along with PD-L1 (the main PD-1 ligand) (26% of total T-cell population). In addition, PD-L1 is also highly expressed on the peptide loaded dendritic cells (about 98% of total mature dendritic cell population) that are used to stimulate the T cells, thereby offering an explanation for the acquisition of dysfunctional features in ex vivo expanded antigen-specific T cells upon repeated antigen exposure.
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