TLR8 ligation induces apoptosis of monocytic myeloid-derived suppressor cells.
TLR8 ligation induces apoptosis of monocytic myeloid-derived suppressor cells.
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DOI：
10.1002/jlb.5ab0217-070r
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发表时间：
2018-01
影响因子：
5.5
通讯作者：
Disis ML
中科院分区：
文献类型：
--
作者：
Dang Y;Rutnam ZJ;Dietsch G;Lu H;Yang Y;Hershberg R;Disis ML
骨髓源性抑制细胞（MDSC）在肿瘤和癌症患者的外周血中积累，并在多种肿瘤类型中表现出促癌活性。已知影响MDSC活性的药剂数量有限。Toll样受体（TLR）8在骨髓细胞中表达。我们研究了TLR 8在MDSC上的表达以及TLR 8激动剂Motolimod对MDSC存活和功能的影响。TLR 8在单核细胞MDSC（mMDSC）中高度表达，但在粒细胞MDSC（gMDSC）中不表达。与对照相比，用Motolimod处理人PBMC降低了志愿者和癌症供体中mMDSC的水平（p<0.001）。Motolimod不影响gMDSC的水平。mMDSC的减少是由于TLR 8连接诱导的细胞死亡。与对照相比，用FAS中和抗体预处理PBMC抑制Motolimod诱导的mMDSC减少（p<0.001）。最后，我们证明了mMDSC通过CD 3/CD 28活化的T细胞阻碍IL-2分泌，当细胞与Motolimod共培养时，IL-2分泌部分恢复（142±36 pg/ml对59±13 pg/ml; p=0.03）。越来越多的证据表明，MDSC通过抑制肿瘤导向的T细胞促进癌症的进展。TLR 8激动剂可以与癌症免疫方法协同作用以增强适应性免疫应答的抗肿瘤作用。TLR 8在单核细胞髓源性抑制细胞中表达，并且TLR 8激动剂Motolimod可以降低mMDSC的水平并恢复受抑制的T细胞功能。
Myeloid-derived suppressor cells (MDSC) accumulate in tumors and the peripheral blood of cancer patients and demonstrate cancer-promoting activity across multiple tumor types. A limited number of agents are known to impact MDSC activity. Toll-like receptor (TLR) 8 is expressed in myeloid cells. We investigated expression of TLR8 on MDSC and the effect of a TLR8 agonist, Motolimod, on MDSC survival and function. TLR8 was highly expressed in monocytic MDSC (mMDSC) but absent in granulocytic MDSC (gMDSC). Treatment of human PBMC with Motolimod reduced the levels of mMDSC in volunteers and cancer donors vs. control (p<0.001). Motolimod did not impact levels of gMDSC. The reduction of mMDSC was due to induced cell death by TLR8 ligation. Pre-treatment of PBMC with a FAS neutralizing antibody inhibited Motolimod induced reduction of mMDSC compared to control (p<0.001). Finally, we demonstrated that mMDSC impeded IL-2 secretion by CD3/CD28 activated T-cells, IL-2 secretion was partially restored when cells were co-cultured with Motolimod (142±36 pg/ml vs. 59±13 pg/ml; p=0.03). There is increasing evidence that MDSC contribute to the progression of cancer by inhibiting tumor-directed T-cells. TLR8 agonists may synergize with cancer immunotherapeutic approaches to enhance the anti-tumor effects of the adaptive immune response. TLR8 is expressed in monocytic myeloid-derived suppressor cells and TLR8 agonist Motolimod can reduce the levels of mMDSC and restore inhibited T cell function.