title: 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 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.
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ishibashi
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan. tam@nms.ac.jp.
authors.forename: Hideto
authors.initials: H
authors.lastname: Tamura
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Sunakawa
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Asaka
authors.initials: A
authors.lastname: Kondo-Onodera
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Namiko
authors.initials: N
authors.lastname: Okuyama
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Department of Microbiology and Immunology, Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Inhak
authors.initials: I
authors.lastname: Choi
authors.affiliation: Department of Immunology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Koiti
authors.initials: K
authors.lastname: Inokuchi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D061026:Programmed Cell Death 1 Receptor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt