Abstract
Immunotherapy is revolutionizing the treatment paradigm for multiple myeloma (MM). Interferon (IFN)-γ is essential for immune responses, whereas immune checkpoint molecules, such as programmed cell death-1 ligand-1 (PD-L1), mitigate the beneficial anti-tumor immune responses. As HDAC inhibitors alter the immunogenicity and anti-tumor immune responses, we here explored the regulation of PD-L1 expression in MM cells by the clinically available HDAC inhibitor panobinostat in the presence of IFN-γ. IFN-γ activated the STAT1-IRF1 pathway to upregulate PD-L1 expression in MM cells, and panobinostat was able to upregulate their PD-L1 expression without activating the STAT1-IRF1 pathway. Of note, panobinostat enhanced IFN-γR1 expression, which substantially increased the total and phosphorylated levels of STAT1 protein but reduced IRF1 protein levels through proteasomal degradation in the presence of IFN-γ. Panobinostat further enhanced the IFN-γ-mediated durable STAT1 activation in MM cells; STAT1 gene silencing abolished the PD-L1 upregulation by panobinostat and IFN-γ in combination, indicating a critical role for STAT1. These results suggest that panobinostat enhances PD-L1 expression by facilitating the IFN-γ-STAT1 pathway in a ligand-dependent manner in MM cells with ambient IFN-γ. PD-L1 upregulation should be taken into account when combining immunotherapies with panobinostat.
Highlights
Multiple myeloma (MM) progresses while deteriorating immune surveillance
We demonstrated that panobinostat alone upregulated cytotoxicity-associated molecules, including natural killer group 2D (NKG2D) ligands, UL16-binding protein-2/5/6 (ULBP2/5/6), and MHC class I chain–related proteins A and B (MICA/B) in MM cells in parallel with PD-L1 upregulation
The knockdown of signal transducer and activator of transcription 1 (STAT1) (Figure 1C) or interferon regulatory factor-1 (IRF1) (Figure 1D) gene marginally affected the basal expression of PD-L1, but was able to abolish the upregulation of programmed cell death-1 ligand-1 (PDL1) on the surface of KMS-11 cells upon treatment with IFN-γ
Summary
Multiple myeloma (MM) progresses while deteriorating immune surveillance. The recent development of immunotherapies with therapeutic monoclonal antibodies has revolutionized the treatment paradigm for MM [1]. The upregulation of CD38 on the surface of MM cells upon treatment with panobinostat has been recently reported [2]; combinatory treatment of therapeutic anti-CD38 antibodies with panobinostat is expected. It is envisioned that induction of antigen editing with histone deacetylase (HDAC) inhibitors can be combined with immunotherapies for MM, including therapeutic antibodies or chimeric antigen receptor (CAR) T cells. Among the immune checkpoint molecules, programmed death 1 (PD1), a member of the B7 family of cosignaling molecules, and its associated ligand PD-L1 have drawn considerable attention as therapeutic targets in several types of cancers, and inhibitors for the PD-1/PD-L1 axis are often combined with novel anti-cancer agents to maximize their therapeutic efficacy [6,7,8,9,10]
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