期刊
MOLECULAR ONCOLOGY
卷 11, 期 4, 页码 358-372出版社
WILEY
DOI: 10.1002/1878-0261.12032
关键词
bone marrow stromal cells; chemotherapeutic agents; ERK signaling pathway; immune suppression; programmed death ligand 1
类别
资金
- National Natural Science Foundation of China [81430060, 81502573]
- Natural Science Foundation of Guangdong Province [2014A030310421]
- Guangzhou Medicare Collaborative Innovation Program [201508020250]
- Guangzhou Innovation Research Program [LCY201317]
- Young Teacher Fund of Sun Yat-Sen University [16ykpy20]
Programmed cell death ligand 1 (PD-L1) is a negative regulator of the immune response that enables tumor cells to escape T-cell immunity. Although PD-L1 expression in cancer cells has been extensively studied, the expression of PD-L1 in stromal cells and its clinical significance remain largely unknown. Here, we show that bone marrow stromal cells express a low level of PD-L1 and that this molecule is significantly upregulated by key drugs used in the treatment of lymphoma at clinically relevant concentrations. Mechanistically, chemotherapeutic drugs induce PD-L1 expression in stromal cells through upregulation of granulocyte macrophage colony-stimulating factor and activation of the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. Suppression of ERK by a chemical inhibitor or genetic silencing of ERK2 expression prevents drug-induced PD-L1 expression. PD-L1 expression is upregulated in the bone marrow stromal cells of mice treated with doxorubicin and in drug-treated bone marrow specimens from lymphoma patients. Drug-induced PD-L1 expression in stromal cells can cause significant impairment of T-cell functions. Overall, our study reveals a previously unrecognized mechanism by which chemotherapy induces tumor immune evasion by upregulation of PD-L1 in bone marrow stromal cells, and provides new evidence for the combination of chemotherapy and anti-PD-L1/PD-1 as an effective strategy for treatment of lymphoma and other cancers.
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