Monophosphoryl lipid A-induced activation of plasmacytoid dendritic cells enhances the anti-cancer effects of anti-PD-L1
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ORIGINAL ARTICLE
Monophosphoryl lipid A‑induced activation of plasmacytoid dendritic cells enhances the anti‑cancer effects of anti‑PD‑L1 antibodies Wei Zhang1 · Seong‑Min Lim2,3 · Juyoung Hwang1,2,3 · Srinivasan Ramalingam4 · Myunghee Kim3,4 · Jun‑O Jin1,2,3 Received: 6 May 2020 / Accepted: 31 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Anti-PD-L1 antibody · MPLA · Anti-cancer · Plasmacytoid dendritic cell · Interferon-alpha Abbreviations Ab Antibody DC Dendritic cell CTLA-4 Cytotoxic T lymphocyte antigen-4 CTL Cytotoxic T lymphocyte cDC Conventional DC IFN Interferon IRF Interferon regulatory factor MPLA Monophosphoryl lipid A PD-1 Programmed cell death protein PD-L1 PD ligand 1 pDC Plasmacytoid DC Wei Zhang and Seong-Min Lim contributed equally to the work. * Jun‑O Jin [email protected] 1
Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai 201508, China
2
Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
3
Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea
4
Department of Food Science and Technology, Yeungnam University, Gyeongsan 38541, Republic of Korea
tdLN Tumor draining lymph node TLR Toll-like receptor
Introduction Immunotherapies, including cancer vaccines [1–3], chimeric antigen receptor (CAR) T cell therapy [4, 5], and immune checkpoint blockades [6], are being developed to effectively treat cancer. Immune checkpoint proteins such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) confer immune tolerance to healthy cells, thus preventing their destruction by immune cells [7–9]. It has previously been reported that cancer cells evade recognition and attack by cytotoxic T lymphocytes (CTLs) via the expression of immune checkpoint proteins
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