title: Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma.
abstract: OBJECTIVE
  PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu.
  
  
  METHODS
  Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138(+) multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti-multiple myeloma immune response and tumor cell growth.
  
  
  RESULTS
  Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression.
  
  
  CONCLUSIONS
  Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti-multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. gullu_gorgun@dfci.harvard.edu kenneth_anderson@dfci.harvard.edu.
authors.forename: Güllü
authors.initials: G
authors.lastname: Görgün
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Biostatistics and Computational Biology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Mehmet K
authors.initials: MK
authors.lastname: Samur
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kristen B
authors.initials: KB
authors.lastname: Cowens
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Steven
authors.initials: S
authors.lastname: Paula
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Giada
authors.initials: G
authors.lastname: Bianchi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Anderson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Randie E
authors.initials: RE
authors.lastname: White
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ahaana
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ohguchi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rikio
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Laubach
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.affiliation: Inserm UMR892, CNRS 6299, Université de Nantes, Nantes, France. Centre Hospitalier Universitaire de Nantes, Unité Mixte de Genomique du Cancer, Nantes, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Magrangeas
authors.affiliation: Inserm UMR892, CNRS 6299, Université de Nantes, Nantes, France. Centre Hospitalier Universitaire de Nantes, Unité Mixte de Genomique du Cancer, Nantes, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Minvielle
authors.affiliation: Unite de Genomique du Myelome, CHU Rangueil, Toulouse, France.
authors.forename: Herve
authors.initials: H
authors.lastname: Avet-Loiseau
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Boston VA Health Care System, Boston, Massachusetts.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: David M
authors.initials: DM
authors.lastname: Dorfman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. gullu_gorgun@dfci.harvard.edu kenneth_anderson@dfci.harvard.edu.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D013792:Thalidomide; D007371:Interferon-gamma; D000077269:Lenalidomide