PD-L1 over-expression is driven by B-cell receptor signaling in diffuse large B-cell lymphoma
Journal
Laboratory Investigation
Journal Volume
99
Journal Issue
10
Pages
1418-1427
Date Issued
2019
Author(s)
Abstract
Targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway represents a milestone in cancer therapy. However, the biologic features of diffuse large B-cell lymphoma (DLBCL) with PD-L1 expression remains unknown. We evaluated the correlation between pSYK and PD-L1 mRNA levels with RNAscope in situ hybridization and protein levels with immunohistochemistry in 108 cases of DLBCL, 25 of which featured loss of B-cell receptor (BCR), and investigated the effects of BCR signaling and MYC on PD-L1 mRNA and protein level with qPCR, immunoblotting and flow cytometery in DLBCL cell lines. PD-L1 amplification was detected with fluorescent in situ hybridization. Animal studies were applied to validate the in vitro findings. pSYK and MYC correlated with both PD-L1 mRNA and protein level. Genetic aberrations involving PD-L1 were rare in DLBCL. BCR signaling and MYC increased PD-L1 mRNA and protein expression. Inhibition of BCR signaling and BCR knockdown down-regulated PD-L1. DLBCL with a loss of loss of BCR showed low levels of PD-L1 mRNA and protein. PD-L1 was down-regulated by ibrutinib in a xenograft mouse model and correlated with slower tumor growth. In conclusion, this study demonstrates that DLBCL with PD-L1 expression features an activated B-cell receptor signal pathway, and that BCR inhibition and PD-L1 blockage may potentially synergize to targeting DLBCL. © 2019, United States & Canadian Academy of Pathology.
SDGs
Other Subjects
B lymphocyte receptor; ibrutinib; lymphocyte membrane immunoglobulin; messenger RNA; Myc protein; programmed death 1 ligand 1; protein kinase Syk; CD274 protein, human; Cd274 protein, mouse; lymphocyte antigen receptor; Myc protein; programmed death 1 ligand 1; protein kinase Syk; pyrazole derivative; pyrimidine derivative; animal experiment; animal model; animal tissue; Article; cell surface; controlled study; diffuse large B cell lymphoma; diffuse large B-cell lymphoma cell line; down regulation; female; gene rearrangement; human; immunoblotting; immunohistochemistry; immunophenotyping; in situ hybridization; in vitro study; mouse; nonhuman; oxidative phosphorylation; priority journal; protein expression; retrospective study; RNA extraction; signal transduction; tumor microenvironment; adult; aged; animal; diffuse large B cell lymphoma; male; metabolism; middle aged; SCID mouse; very elderly; young adult; Adult; Aged; Aged, 80 and over; Animals; B7-H1 Antigen; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Mice, SCID; Middle Aged; Proto-Oncogene Proteins c-myc; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Retrospective Studies; Signal Transduction; Syk Kinase; Young Adult
Type
journal article