title: Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand 1 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.
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Mengqi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.|Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.|Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Kefeng
authors.initials: K
authors.lastname: Wang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Christophe
authors.initials: C
authors.lastname: Glorieux
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Wen
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.|Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D019139:Tumor Escape / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: ERK signaling pathway; bone marrow stromal cells; chemotherapeutic agents; immune suppression; programmed death ligand 1