Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma

Clin Cancer Res. 2015 Oct 15;21(20):4607-18. doi: 10.1158/1078-0432.CCR-15-0200. Epub 2015 May 15.


Purpose: 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.

Experimental design: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • B7-H1 Antigen / metabolism
  • Bone Marrow / drug effects
  • Bone Marrow / immunology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Interferon-gamma / metabolism
  • Lenalidomide
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / immunology*
  • Programmed Cell Death 1 Receptor / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology


  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • RNA, Messenger
  • Thalidomide
  • Interferon-gamma
  • Lenalidomide