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ORIGINAL RESEARCH ARTICLE
Front. Immunol., 27 February 2018 | https://doi.org/10.3389/fimmu.2018.00385
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Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells

Felix S. Lichtenegger^1,2†, Maurine Rothe^1,2†, Frauke M. Schnorfeil^1,2,3, Katrin Deiser^1,2, Christina Krupka^1,2, Christian Augsberger^1,2, Miriam Schlüter^1,2, Julia Neitz^1,2 and Marion Subklewe^1,2,3*

• ¹Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
• ²Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany
• ³German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

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.

This was a rather involved research paper that got a bit too involved for me but
I certainly understood the first paragraph....Very recent too.......