1. Durvalumab Combined with Immunomodulatory Drugs (IMiD) Overcomes Suppression of Antitumor Responses due to IMiD-induced PD-L1 Upregulation on Myeloma Cells.
- Author
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Ishibashi M, Yamamoto J, Ito T, Handa H, Sunakawa-Kii M, Inokuchi K, Morita R, and Tamura H
- Subjects
- Animals, Apoptosis drug effects, B-Cell Maturation Antigen metabolism, B7-H1 Antigen metabolism, Cell Line, Tumor, Cell Survival drug effects, Disease Models, Animal, Gene Knockdown Techniques, Humans, Ikaros Transcription Factor metabolism, Immunophenotyping, Mice, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, Multiple Myeloma pathology, Programmed Cell Death 1 Receptor, Proteolysis, Signal Transduction drug effects, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tumor Necrosis Factor Ligand Superfamily Member 13 metabolism, Xenograft Model Antitumor Assays, Antibodies, Monoclonal pharmacology, Antineoplastic Agents, Immunological pharmacology, B7-H1 Antigen genetics, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic drug effects, Immunomodulating Agents pharmacology, Multiple Myeloma genetics
- Abstract
We previously showed that the interaction of programmed death-ligand 1 (PD-L1) on multiple myeloma (MM) cells with PD-1 not only inhibits tumor-specific cytotoxic T-lymphocyte activity via the PD-1 signaling pathway but also induces drug resistance via PD-L1-mediated reverse signals. We here examined the regulation of PD-L1 expression by immunomodulatory drugs (IMiDs) and antimyeloma effects of the anti-PD-L1 antibody durvalumab in combination with IMiDs. IMiDs induced PD-L1 expression on IMiD-insensitive MM cells and plasma cells from patients newly diagnosed with MM. Gene-expression profiling analysis demonstrated that not only PD-L1, but also a proliferation-inducing ligand (APRIL), was enhanced by IMiDs. PD-L1 induction by IMiDs was suppressed by using the APRIL inhibitor recombinant B-cell maturation antigen (BCMA)-Ig, the antibody against BCMA, or an MEK/ERK inhibitor in in vitro and in vivo assays. In addition, its induction was abrogated in cereblon (CRBN)-knockdown MM cells, whereas PD-L1 expression was increased and strongly induced by IMiDs in Ikaros-knockdown cells. These results demonstrated that PD-L1 upregulation by IMiDs on IMiD-insensitive MM cells was induced by (i) the BCMA-APRIL pathway via IMiD-mediated induction of APRIL and (ii) Ikaros degradation mediated by CRBN, which plays a role in inhibiting PD-L1 expression. Furthermore, T-cell inhibition induced by PD-L1-upregulated cells was effectively recovered after combination treatment with durvalumab and IMiDs. PD-L1 upregulation by IMiDs on MM cells might promote aggressive myeloma behaviors and immune escape in the bone marrow microenvironment., (©2021 American Association for Cancer Research.)
- Published
- 2021
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