title: Generation of antitumor invariant natural killer T cell lines in multiple myeloma and promotion of their functions via lenalidomide: a strategy for immunotherapy.
abstract: OBJECTIVE
  CD1d-restricted invariant natural killer T (iNKT) cells are important immunoregulatory cells in antitumor immune responses. However, the quantitative and qualitative defects of iNKT cells in advanced multiple myeloma hamper their antitumor effects. Therefore, the development of functional iNKT cells may provide a novel strategy for the immunotherapy in multiple myeloma.
  
  
  METHODS
  We activated and expanded iNKT cells from multiple myeloma patients with alpha-galactosylceramide (alpha-GalCer)-pulsed dendritic cells, characterized their antitumor effects by the cytokine production profile and cytotoxicity against multiple myeloma cells, and explored the effects of immunomodulatory drug lenalidomide on these iNKT cells. We also investigated the expression of CD1d by primary multiple myeloma cells and its function to activate iNKT cells.
  
  
  RESULTS
  We established highly purified functional iNKT cell lines from newly diagnosed and advanced multiple myeloma patients. These CD1d-restricted iNKT cell lines produced high level of antitumor Th1 cytokine in response to alpha-GalCer-pulsed primary multiple myeloma cells, CD1d-transfected MM1S cell line, and dendritic cells. Moreover, iNKT cell lines displayed strong cytotoxicity against alpha-GalCer-pulsed primary multiple myeloma cells. Importantly, lenalidomide further augmented the Th1 polarization by iNKT cell lines via increased Th1 cytokine production and reduced Th2 cytokine production. We also showed that CD1d was expressed in primary multiple myeloma cells at mRNA and protein levels from the majority of multiple myeloma patients, but not in normal plasma cells and multiple myeloma cell lines, and CD1d(+) primary multiple myeloma cells presented antigens to activate iNKT cell lines.
  
  
  CONCLUSIONS
  Taken together, our results provide the preclinical evidence for the iNKT cell-mediated immunotherapy and a rationale for their use in combination with lenalidomide in multiple myeloma treatment.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Song
authors.forename: Hans J J
authors.initials: HJ
authors.lastname: van der Vliet
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Rao
authors.initials: R
authors.lastname: Prabhala
authors.forename: Ruojie
authors.initials: R
authors.lastname: Wang
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Laurence
authors.initials: L
authors.lastname: Catley
authors.forename: Masood A
authors.initials: MA
authors.lastname: Shammas
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.forename: Mark A
authors.initials: MA
authors.lastname: Exley
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
mesh_terms: D018949:Antigens, CD1 / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000276:immunology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018949:Antigens, CD1; D013792:Thalidomide; D000077269:Lenalidomide