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 bead-treated 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 tumor-specific 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. Cancer Immunol Res; 4(9); 779-88. ©2016 AACR.
Highlights
B7 homolog 1 (B7-H1), known as programmed deathligand 1 (PD-L1) or CD274, is an immune checkpoint molecule belonging to the B7 family and is detected on many different tumor cells, such as hepatocellular, breast, pancreatic, colon, and renal cell carcinomas, and hematologic malignancies [1,2,3,4]
To investigate whether the reverse signal resulting from B7-H1 binding to programmed cell death (PD)-1 or CD80 induced aggressive behavior in B7-H1–expressing myeloma cells, we examined the cell cycle, BrdUrd incorporation, and apoptosis resistance induced by antimyeloma agents when MOSTI-1 cells were cocultured with beads coated with control Ig, CD80-Fc, or programmed cell death 1 (PD-1)-Fc
Tumor-associated B7-H1 molecules transmit inhibitory signals to tumor-specific cytotoxic T lymphocyte (CTL) via the B7-H1–PD-1 pathway, which contributes to tumor immune escape [9, 32]
Summary
B7 homolog 1 (B7-H1), known as programmed deathligand 1 (PD-L1) or CD274, is an immune checkpoint molecule belonging to the B7 family and is detected on many different tumor cells, such as hepatocellular, breast, pancreatic, colon, and renal cell carcinomas, and hematologic malignancies [1,2,3,4]. CTLs via the B7-H1–PD-1 interaction, resulting in T-cell apoptosis in vitro and in vivo, and the B7-H1–PD-1 interaction attenuates activated tumor-infiltrating T cells through the inhibition of T-cell receptor (TCR) signaling [1, 4, 11, 12]. B7-H1 molecules can transmit an inhibitory signal to CD80-expressing T cells via the B7-H1– CD80 interaction [13], the role of that interaction in tumor immunity has not been clarified. Research on B7-H1– PD-1 interactions in the tumor microenvironment is focused on a new target for immunotherapy in patients with various types of cancer who show high B7-H1 expression on tumor cells. Blockade of the B7-H1– PD-1 pathway using antibodies to PD-1 or to B7-H1 markedly improves survival in some B7-H1–positive patients with non– small cell lung, prostate, and renal cell cancer, and melanoma [20,21,22]
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