Shi Yongyu, Felder Mildred A R, Sondel Paul M, Rakhmilevich Alexander L
Institute of Immunology, Shandong University School of Medicine, Jinan, China; University of Wisconsin, Department of Human Oncology, Madison, WI, USA.
University of Wisconsin, Department of Obstetrics and Gynecology, Madison, WI, USA.
Mol Immunol. 2015 Aug;66(2):208-15. doi: 10.1016/j.molimm.2015.03.008. Epub 2015 Mar 28.
Activation of macrophages is a prerequisite for their antitumor effects. Several reagents, including agonistic anti-CD40 monoclonal antibody (anti-CD40), CpG oligodeoxynucleotides (CpG) and monophosphoryl lipid A (MPL), can stimulate activation of macrophages. Our previous studies showed synergy between anti-CD40 and CpG and between anti-CD40 and MPL in macrophage activation and antitumor efficacy in mice. In the present study, we asked whether there was synergy among these three reagents. The activation of adherent peritoneal exudate cells (PEC) obtained from mice injected with anti-CD40 and then treated with CpG and/or MPL in vitro was determined by their ability to suppress proliferation of tumor cells and to produce various cytokines and chemokines in vitro. Cell sorting and histology followed by functional testing showed that macrophages were the main cell population in PEC activated by CD40 ligation in vivo. A combination of anti-CD40, CpG or MPL activated PEC to suppress proliferation of B16 cells and produce nitric oxide far greater than the single reagents or any of the double combinations of these reagents. In addition, the combination of all three reagents activated PEC to secrete IL-12, IFN-γ and MCP-1 to a greater degree than any single reagent or any two combined reagents. These results demonstrate that macrophages can be synergistically activated by anti-CD40, CpG and MPL, suggesting that this novel combined approach might be further investigated as potential cancer therapy.
巨噬细胞的激活是其发挥抗肿瘤作用的前提条件。包括激动性抗CD40单克隆抗体（抗CD40）、CpG寡脱氧核苷酸（CpG）和单磷酰脂质A（MPL）在内的几种试剂，均可刺激巨噬细胞的激活。我们之前的研究表明，在小鼠的巨噬细胞激活和抗肿瘤疗效方面，抗CD40与CpG之间以及抗CD40与MPL之间存在协同作用。在本研究中，我们探究了这三种试剂之间是否存在协同作用。通过体外抑制肿瘤细胞增殖以及产生各种细胞因子和趋化因子的能力，来测定从小鼠体内获取的贴壁腹膜渗出细胞（PEC）的激活情况，这些小鼠先注射抗CD40，然后体外给予CpG和/或MPL处理。细胞分选、组织学检查及随后的功能测试表明，巨噬细胞是体内CD40连接激活的PEC中的主要细胞群体。抗CD40、CpG或MPL联合使用激活的PEC抑制B16细胞增殖和产生一氧化氮的能力，远远大于单一试剂或这些试剂的任何两种组合。此外，三种试剂联合使用激活的PEC分泌IL-12、IFN-γ和MCP-1的程度，比任何单一试剂或任何两种联合试剂都要高。这些结果表明，抗CD40、CpG和MPL可协同激活巨噬细胞，提示这种新型联合方法作为潜在的癌症治疗手段可能值得进一步研究。
