Abstract
Immune checkpoint inhibition has been shown to successfully reactivate endogenous T cell responses directed against tumor-associated antigens, resulting in significantly prolonged overall survival in patients with various tumor entities. For malignancies with low endogenous immune responses, this approach has not shown a clear clinical benefit so far. Therapeutic vaccination, particularly dendritic cell (DC) vaccination, is a strategy to induce T cell responses. Interaction of DCs and T cells is dependent on receptor–ligand interactions of various immune checkpoints. In this study, we analyzed the influence of blocking antibodies targeting programmed cell death protein 1 (PD-1), HVEM, CD244, TIM-3, and lymphocyte activation gene 3 (LAG-3) on the proliferation and cytokine secretion of T cells after stimulation with autologous TLR-matured DCs. In this context, we found that LAG-3 blockade resulted in superior T cell activation compared to inhibition of other pathways, including PD-1/PD-L1. This result was consistent across different methods to measure T cell stimulation (proliferation, IFN-γ secretion), various stimulatory antigens (viral and bacterial peptide pool, specific viral antigen, specific tumor antigen), and seen for both CD4+ and CD8+ T cells. Only under conditions with a weak antigenic stimulus, particularly when combining antigen presentation by peripheral blood mononuclear cells with low concentrations of peptides, we observed the highest T cell stimulation with dual blockade of LAG-3 and PD-1 blockade. We conclude that priming of novel immune responses can be strongly enhanced by blockade of LAG-3 or dual blockade of LAG-3 and PD-1, depending on the strength of the antigenic stimulus.
Highlights
Immunotherapy has changed our approach to anti-cancer treatment in recent years
toll-like receptor (TLR)-3-dendritic cell (DC) were generated from peripheral blood (PB) of healthy donor (HD)
HLA-DR was added to the panel as ligand for lymphocyte activation gene 3 (LAG-3) on T cells
Summary
Immunotherapy has changed our approach to anti-cancer treatment in recent years. Checkpoint inhibitors have been in the focus of clinical development and have shown remarkable success as monotherapy or as combination partners for various tumor entities. We tested the hypothesis that blockade of PD-1 and LAG-3 has additive or synergistic effects on proliferation or IFN-γ secretion by T cells after stimulation with TLR-3-DCs. For proliferation assays, CD3+ T cells isolated from PB of 7 HDs were labeled with CFSE and cocultured with autologous TLR-3-DCs for 5 days in the presence or absence of blocking antibodies for PD-1 and LAG-3, both alone and in combination.
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