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

Autor: Andrea van Elsas, John Dulos, Chirag Acharya, Phillip A Hsieh, Paul G. Richardson, Nikhil C. Munshi, Yu-Tzu Tai, Tengteng Yu, Shih-Feng Cho, Kenneth Wen, Lijie Xing, Kenneth C. Anderson, Liang Lin
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Transmembrane Activator and CAML Interactor Protein
medicine.medical_treatment
interleukin-10
Osteoclasts
T-Lymphocytes
Regulatory
0302 clinical medicine
Osteoclast (OC)
multiple myeloma (MM)
Cells
Cultured
Multiple myeloma
biology
Antibodies
Monoclonal
FOXP3
conventional T (Tcon)
Immunosuppression
Hematology
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
IL-10
Transmembrane Activator and CAML Interactor (TACI)
Antibody
Multiple Myeloma
Immunosuppressive Agents
Signal Transduction
regulatory T (Treg)
medicine.drug_class
Tumor Necrosis Factor Ligand Superfamily Member 13
chemical and pharmacologic phenomena
Monoclonal antibody
Article
TGFβ
03 medical and health sciences
Immune system
Downregulation and upregulation
Biomarkers
Tumor
Immune Tolerance
tumor-induced Treg (iTregs)
medicine
Humans
Immunosuppression Therapy
A proliferation inducing ligand (APRIL)
business.industry
tumor growth factor beta
medicine.disease
030104 developmental biology
Cancer research
biology.protein
Bone marrow
business
Zdroj: Leukemia
ISSN: 1476-5551
0887-6924
Popis: 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.
Databáze: OpenAIRE
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