Targeting Immune Checkpoints to Enhance T cell Activation by Antigen-Presenting Cells: Blockade of LAG-3 is the Most Effective Maurine Rothe1,2, Felix S. Lichtenegger1,2, Frauke M. Schnorfeil1,2, Katrin Deiser1,2, Christina Krupka1,2, Christian Augsberger1,2, Miriam Schlüter1,2, Julia Neitz1,2 and Marion Subklewe1,2,3 1Department of Medicine III, University Hospital, LMU Munich, Germany 2 Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Germany 3 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Immune checkpoint blockade has been demonstrated to successfully reactivate endogenous T cell responses directed against tumor-associated antigens, increasing overall survival of patients with various cancer types. For cancers with low endogenous immune responses, this approach has not yet shown a striking clinical benefit. A strategy to induce T cell responses is therapeutic vaccination, in particular dendritic cell vaccination. Interaction of dendritic cells and T cells is dependent on ligand-receptor interactions of various immune checkpoints. We analyzed the influence of blocking antibodies targeting the inhibitory immune checkpoints PD-1, HVEM, CD244, TIM-3, and LAG-3 on the proliferation and cytokine secretion of T cells after stimulation with autologous TLR-matured dendritic cells. In this context, we found that LAG-3 blockade resulted in superior T cell activation compared to inhibition of other pathways including the PD-1/PD-L1 axis. This result was consistent using different methods to measure T cell activation (proliferation, IFN-γ secretion), various stimulatory antigens (viral and bacterial peptide pool, specific viral antigen, specific tumor antigen), and observed for both CD4+ and CD8+ T cells. Only under conditions with a weak antigenic stimulus, particularly when combining antigen presentation by PBMCs with low concentrations of peptides, we observed the highest T cell stimulation with the combinatorial blockade of LAG-3 and PD-1. Thus, we conclude that priming of novel immune responses can be strongly enhanced by blockade of LAG-3 or combinatorial blockade of LAG-3 and PD-1, depending on the strength of antigenic stimulus.
This work was supported by the international doctoral program “i-Target: Immunotargeting of cancer” funded by the Elite Network of Bavaria