Myeloma Drug Resistance Induced by Binding of Myeloma B7-H1 (PD-L1) to PD-1

Abstract

B7 homolog 1 (B7-H1)-expressing myeloma cells not only inhibit myeloma-specific cytotoxic T lymphocytes (CTL), but also confer a proliferative advantage: resistance to antimyeloma chemotherapy. However, it remains unknown whether B7-H1 expressed on myeloma cells induces cellular responses associated with aggressive myeloma behaviors. To address this question, we analyzed the proliferation and drug sensitivity of B7-H1-expressing myeloma cells transfected with B7-H1-specific short-hairpin RNA or treated with programmed cell death (PD)-1-Fc-coupled beads. Knockdown of B7-H1 expression in myeloma cells significantly inhibited cell proliferation and increased apoptosis induced by the chemotherapeutic alkylating agent melphalan, with downregulation of the expression of cell cycle-related genes (CCND3 and CDK6) and antiapoptotic genes (BCL2 and MCL1). B7-H1 molecules thus contributed to myeloma cell-cycle progression and suppression of drug-induced apoptosis. B7-H1-expressing myeloma cells had a higher affinity for PD-1 than for CD80. PD-1-Fc beadtreated myeloma cells also became resistant to apoptosis that was induced by melphalan and the proteasome inhibitor bortezomib. Apoptosis resistance was associated with the PI3K/AKT pathway. Both myeloma cell drug resistance and antiapoptotic responses occurred through the PI3K/AKT signaling pathway, initiated from "reverse" stimulation of B7-H1 by PD-1. Therefore, B7-H1 itself may function as an oncogenic protein in myeloma cells. The interaction between B7-H1 on myeloma cells and PD-1 molecules not only inhibits tumorspecific CTLs but also induces drug resistance in myeloma cells through the PI3K/AKT signaling pathway. These observations provide mechanistic insights into potential immunotherapeutic benefits of blocking the B7-H1-PD-1 pathway.

Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma

“…[5][6][7] PD-L1 expression has been shown to induce drug resistance in myeloma cell lines through the PI3K/Akt signaling pathway. 8 PD-L1 expression on antigen-presenting dendritic cells (DCs) and myeloid-derived suppressor cells provide a tumor-promoting, immune-suppressive microenvironment in MM.…”

CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/Cyclin D2 signaling

“…Therefore, we speculate that there also exists a bi-directional signaling upon PD-1/PD-L1 interaction. Consistently, Ishibashi et al also provide intriguing evidence that CD274 can function as an oncogene to enhance the proliferation and inhibit the apoptosis of myeloma cells [34]. …”

Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality?

“…PD-L1 expression is associated with increased proliferation and increased resistance to anti-myeloma therapy. 43 PD-L1 expression on plasma cells is upregulated in the setting of relapsed and refractory disease, which suggests that it might have a role in the development of clonal resistance. 44 The mechanisms by which PD-L1 expression is regulated are currently an area of investigation.…”