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

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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.

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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

tdLN:

Tumor draining lymph node

TLR:

Toll-like receptor

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Acknowledgements

We thank SPHCC animal facility for maintaining the animals in this study.

Funding

This study was supported by the Research fund of the National Research Foundation of Korea (NRF-2019R1C1C1003334 and NRF-2020R1A6A1A03044512).

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Author notes

  1. Wei Zhang and Seong-Min Lim contributed equally to the work.

Authors and Affiliations

  1. Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, China

    Wei Zhang, Juyoung Hwang & Jun-O Jin

  2. Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 38541, Republic of Korea

    Seong-Min Lim, Juyoung Hwang & Jun-O Jin

  3. Research Institute of Cell Culture, Yeungnam University, Gyeongsan, 38541, Republic of Korea

    Seong-Min Lim, Juyoung Hwang, Myunghee Kim & Jun-O Jin

  4. Department of Food Science and Technology, Yeungnam University, Gyeongsan, 38541, Republic of Korea

    Srinivasan Ramalingam & Myunghee Kim

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  1. Wei Zhang
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Contributions

Conceptualization, JOJ; formal analysis, JOJ; data curation, WZ, SML, ST, MK and JOJ; original draft preparation, SML and JOJ; writing-review and editing, MK and JOJ. All authors approved the manuscript.

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Correspondence to Jun-O Jin.

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Zhang, W., Lim, SM., Hwang, J. et al. Monophosphoryl lipid A-induced activation of plasmacytoid dendritic cells enhances the anti-cancer effects of anti-PD-L1 antibodies. Cancer Immunol Immunother 70, 689–700 (2021). https://doi.org/10.1007/s00262-020-02715-4

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