APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications

Leukemia. 2019 Feb;33(2):426-438. doi: 10.1038/s41375-018-0242-6. Epub 2018 Aug 22.


We investigate here how APRIL impacts immune regulatory T cells and directly contributes to the immunosuppressive multiple myeloma (MM) bone marrow (BM) microenvironment. First, APRIL receptor TACI expression is significantly higher in regulatory T cells (Tregs) than conventional T cells (Tcons) from the same patient, confirmed by upregulated Treg markers, i.e., Foxp3, CTLA-4. APRIL significantly stimulates proliferation and survival of Tregs, whereas neutralizing anti-APRIL monoclonal antibodies (mAbs) inhibit these effects. Besides TACI-dependent induction of cell cycle progression and anti-apoptosis genes, APRIL specifically augments Foxp3, IL-10, TGFβ1, and PD-L1 in Tregs to further enhance Treg-inhibited Tcon proliferation. APRIL further increases MM cell-driven Treg (iTreg) via TACI-dependent proliferation associated with upregulated IL-10, TGFβ1, and CD15s in iTreg, which further inhibits Tcons. Osteoclasts producing APRIL and PD-L1 significantly block Tcon expansion by iTreg generation, which is overcome by combined treatment with anti-APRIL and anti-PD1/PD-L1 mAbs. Finally, APRIL increases IL-10-producing B regulatory cells (Bregs) via TACI on BM Bregs of MM patients. Taken together, these results define novel APRIL actions via TACI on Tregs and Bregs to promote MM cell survival, providing the rationale for targeting APRIL/TACI system to alleviate the immunosuppressive BM milieu and improve patient outcome in MM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cells, Cultured
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Tolerance / immunology*
  • Immunosuppression Therapy*
  • Immunosuppressive Agents / pharmacology
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / immunology*
  • Multiple Myeloma / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / drug effects
  • Osteoclasts / immunology*
  • Osteoclasts / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • Transmembrane Activator and CAML Interactor Protein / genetics
  • Transmembrane Activator and CAML Interactor Protein / metabolism*
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / genetics
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism*


  • Antibodies, Monoclonal
  • Biomarkers, Tumor
  • Immunosuppressive Agents
  • TNFRSF13B protein, human
  • TNFSF13 protein, human
  • Transmembrane Activator and CAML Interactor Protein
  • Tumor Necrosis Factor Ligand Superfamily Member 13