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Front. Immunol. | doi: 10.3389/fimmu.2018.00385

Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells

 Felix S. Lichtenegger1, 2,  Maurine Rothe1, 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
  • 2Gene Center, LMU Munich, Germany
  • 3German Cancer Consortium, German Cancer Research Center (DKFZ), 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 vaccination, is a strategy to induce T cell responses. Interaction of dendritic cells and T cells is dependent on receptor-ligand interactions of various immune checkpoints. In this study, we analyzed the influence of blocking antibodies targeting 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 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 PBMCs 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.

Keywords: cancer immunotherapy, dendritic cell, immune checkpoint molecules, LAG-3, PD-1, T cell response

Received: 08 Oct 2017; Accepted: 12 Feb 2018.

Edited by:

Rene De Waal Malefyt, Merck (United States), United States

Reviewed by:

Lawrence Kane, University of Pittsburgh, United States
David Escors, University College London, United Kingdom
Sid P. Kerkar, Boehringer Ingelheim (United States), United States
Lewis Zhichang Shi, Case Western Reserve University, United States  

Copyright: © 2018 Lichtenegger, Rothe, Schnorfeil, Deiser, Krupka, Augsberger, Schlüter, Neitz and Subklewe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Marion Subklewe, University Hospital, LMU Munich, Department of Medicine III, Munich, Germany, Marion.Subklewe@med.uni-muenchen.de