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.
Keywords: ERK signaling pathway; bone marrow stromal cells; chemotherapeutic agents; immune suppression; programmed death ligand 1.
© 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.