title: Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy.
abstract: Multiple myeloma (MM) produces significant cellular and humoral immune defects. We have previously reported that MM induces CD4(+)CD25(+)FoxP3(+) cells (TRegs), via tumour expression of the immune checkpoint regulator, ICOS-L. We sought to define what impact the immunomodulatory drug lenalidomide, alone or with dexamethasone, has on TReg cell generation. Lenalidomide pre-treatment of MM cell lines reduced TReg generation and the concomitant TReg:TEff (CD4(+)CD25(+)FoxP3(-): effector T cells) ratio, as a consequence of reduced ICOSL transcription. Dexamethasone did not affect surface ICOS-L expression but did induce TReg cell apoptosis without impacting on TEff cell survival. Combined lenalidomide and dexamethasone significantly reduced both TReg induction and the TReg:TEff cell ratio. In vivo, serial analysis of the TReg:TEff ratio in MM patients on lenalidomide-dexamethasone therapy revealed a progressive reduction towards age-matched control values, though not complete correction. Our data demonstrate for the first time immune synergism to explain the observed immune-modulation associated with lenalidomide-dexamethasone therapy.
authors.affiliation: Transplant Immunology Group, Section of Experimental Haematology, Leeds Institute of Cancer & Pathology, University of Leeds, United Kingdom.
authors.forename: Gina B
authors.initials: GB
authors.lastname: Scott
authors.affiliation: Department of Clinical Immunology, Leeds Teaching Hospitals Trust, United Kingdom.
authors.forename: Clive
authors.initials: C
authors.lastname: Carter
authors.affiliation: Transplant Immunology Group, Section of Experimental Haematology, Leeds Institute of Cancer & Pathology, University of Leeds, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Parrish
authors.affiliation: Department of Clinical Immunology, Leeds Teaching Hospitals Trust, United Kingdom.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Wood
authors.affiliation: Transplant Immunology Group, Section of Experimental Haematology, Leeds Institute of Cancer & Pathology, University of Leeds, United Kingdom. Electronic address: g.cook@leeds.ac.uk.
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000096:biosynthesis*; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; C498514:ICOSLG protein, human; D007155:Immunologic Factors; D060945:Inducible T-Cell Co-Stimulator Ligand; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide
keywords: Immune checkpoint regulators; Immune-modulatory drugs; Myeloma; Regulatory T-cells