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ORIGINAL RESEARCH ARTICLE
Front. Immunol., 27 February 2018 |
https://doi.org/10.3389/fimmu.2018.00385
mce-anchor
Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells
Felix S. Lichtenegger1,2†,
Maurine Rothe1,2†,
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 Subklewe1,2,3*
- 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.......
