Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, China.
Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
Cancer Immunol Immunother. 2021 Mar;70(3):689-700. doi: 10.1007/s00262-020-02715-4. Epub 2020 Sep 9.
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.
单磷酰脂质 A（MPLA）是一种 Toll 样受体 4 配体，可在小鼠和人类中促进免疫激活，而不会引起不必要的炎症。免疫检查点阻断和 MPLA 的联合免疫疗法已在小鼠和人类中显示出有希望的抗癌作用。在这项研究中，我们探讨了 MPLA 如何增强抗 PD-L1 抗体（Abs）的抗癌作用。在耗尽 CD4 和 CD8 细胞的小鼠中，抗 PD-L1 Abs 和 MPLA 的联合作用不能诱导抗癌免疫。此外，抗 PD-L1 Abs 和 MPLA 的联合治疗在体内协同增强了小鼠浆细胞样树突状细胞（pDCs）的激活，而常规树突状细胞则没有。此外，用抗 PD-L1 Abs 和 MPLA 治疗的小鼠不能通过阻断干扰素-α受体（IFNAR）来预防 B16 黑色素瘤。抗 PD-L1 Abs 和 MPLA 的联合治疗也促进了人外周血 pDC 的激活，并诱导了 IFN-α依赖性 T 细胞的激活。因此，这些结果表明，MPLA 通过 pDC 的激活和 IFN-α 的产生增强了抗 PD-L1 Ab 介导的抗癌免疫。
