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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2021-03, Vol.70 (3), p.689-700
• Main Authors: Zhang, Wei, Lim, Seong-Min, Hwang, Juyoung, Ramalingam, Srinivasan, Kim, Myunghee, Jin, Jun-O
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; B7-H1 Antigen - antagonists & inhibitors; Biomarkers; Cancer; Cancer Research; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cytokines - metabolism; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immunology; Immunophenotyping; Immunotherapy; Inflammation; Interferon; Interferon receptors; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lipid A; Lipid A - analogs & derivatives; Lipid A - pharmacology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes T; Medicine; Medicine & Public Health; Melanoma; Melanoma, Experimental; Mice; Monophosphoryl lipid A; Oncology; Original; Original Article; PD-L1 protein; Peripheral blood; TLR4 protein; Toll-like receptors; α-Interferon
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02715-4

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.