Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand1 expression in bone marrow stromal cells.

Abstract

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.