title: Regulation of multiple myeloma survival and progression by CD1d.
abstract: Down-regulation of conventional human leukocyte antigen (HLA) class I and II molecules from the surface of tumor cells is an important mechanism for tumor immune evasion, survival, and progression. Whether CD1d, a nonconventional, glycolipid-presenting HLA class I-like molecule instructing the function of the immunoregulatory invariant NKT cells can affect tumor cell survival is not known. Here we show that CD1d is highly expressed in premalignant and early myeloma, but with disease progression its expression is reduced and eventually in advanced stages and myeloma cell lines is lost altogether, suggesting that CD1d impacts negatively on myeloma cell survival. Consistent with this, engagement of CD1d by anti-CD1d monoclonal antibodies (mAbs) induces cell death of myeloma cell lines with restored CD1d expression and primary myeloma cells. Cell death induced by monoclonal antibody engagement of CD1d is associated with overexpression of proapoptotic Bax and mitochondrial membrane potential loss but it is caspase-activation independent; in addition, it requires the cytoplasmic tail but not the Tyr residue critical for lysosomal sorting of CD1d. Finally, anti-CD1d cooperates with antimyeloma agents in the killing of myeloma cells. Thus, this work provides evidence linking a novel function of CD1d in the regulation of cell death with tumor survival and progression in humans.
authors.affiliation: Department of Haematology, Imperial College Healthcare National Health Service (NHS) Trust, Hammersmith and St Mary's Hospital, Imperial College London, London, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Spanoudakis
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.forename: Kikkeri
authors.initials: K
authors.lastname: Naresh
authors.forename: Evangelos
authors.initials: E
authors.lastname: Terpos
authors.forename: Valeria
authors.initials: V
authors.lastname: Melo
authors.forename: Alistair
authors.initials: A
authors.lastname: Reid
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kotsianidis
authors.forename: Saad
authors.initials: S
authors.lastname: Abdalla
authors.forename: Amin
authors.initials: A
authors.lastname: Rahemtulla
authors.forename: Anastasios
authors.initials: A
authors.lastname: Karadimitris
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002449:Cell Aggregation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000008:administration & dosage; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D055610:Antigens, CD1d; D001897:Boronic Acids; C526877:CD1D protein, human; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone