Monophosphoryl lipid A-induced activation of plasmacytoid dendritic cells enhances the anti-cancer effects of anti-PD-L1 antibodies.

Abstract

Monophosphoryl lipid A (MPLA) is a toll-like receptor 4 ligand that promotes immune activation in mice and humans, without undesired inflammation. Immunotherapy by the combining immune checkpoint blockade and MPLA has shown promising anti-cancer effects in both mice and humans. In this study, we explored how MPLA enhanced the anti-cancer effects of anti-PD-L1 antibodies (Abs). Anti-cancer immunity induced by the combination of anti-PD-L1 Abs and MPLA failed in CD4 and CD8 cell-depleted mice. Moreover, the combination treatment of anti-PD-L1 Abs and MPLA synergistically enhanced the activation of plasmacytoid dendritic cells (pDCs) in the mouse in vivo, while conventional DCs were not. In addition, mice treated with anti-PD-L1 Abs and MPLA were not protected from B16 melanoma by blockade of interferon-alpha receptor (IFNAR). The combination of anti-PD-L1 Abs and MPLA also promoted human peripheral blood pDC activation and induced IFN-α-dependent T cell activation. Therefore, these results demonstrate that MPLA enhances anti-PD-L1 Ab-mediated anti-cancer immunity through the activation and IFN-α production of pDCs.

• Authors: Wei Zhang, Seong-Min Lim, Juyoung Hwang, Srinivasan Ramalingam, Myunghee Kim, Jun-O Jin
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 70 Issue 3 Pg. 689-700 (Mar 2021) ISSN: 1432-0851 [Electronic] Germany
• PMID: 32902663 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen
• Biomarkers
• CD274 protein, human
• Cytokines
• Immune Checkpoint Inhibitors
• Lipid A
• monophosphoryl lipid A

Topics

• Animals
• B7-H1 Antigen (antagonists & inhibitors)
• Biomarkers
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cytokines (metabolism)
• Dendritic Cells (drug effects, immunology, metabolism)
• Female
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Immunophenotyping
• Leukocytes, Mononuclear (immunology, metabolism)
• Lipid A (analogs & derivatives, pharmacology)
• Lymphocyte Activation (drug effects, immunology)
• Melanoma, Experimental
• Mice