Tumour cell generation of inducible regulatory T-cells in multiple myeloma is contact-dependent and antigen-presenting cell-independent.
Regulatory T-cells (T(Reg) cells) are increased in patients with multiple myeloma (MM). We investigated whether MM cells could generate and/or expand T(Reg) cells as a method of immuno-surveillance avoidance. In an in vitro model, CD4(+)CD25(-)FoxP3(-) T-cells co-cultured with malignant plasma cells (primary MM cells and cell lines) induced a significant generation of CD4(+)CD25(+)FoxP3(+) inducible T(Reg) cells (tT(Reg) cells; p<0.0001), in a contact-dependent manner. tT(Reg) cells were polyclonal, demonstrated a suppressive phenotype and phenotypically, demonstrated increased FoxP3 (p = 0.0001), increased GITR (p<0.0001), increased PD1 (p = 0.003) and decreased CD62L (p = 0.007) expression compared with naturally occurring T(Reg) cells. FACS-sorted tT(Reg) cells differentiated into FoxP(+)IL-17(+) and FoxP3(-)IL-17(+) CD4(+) cells upon TCR-mediated stimulation. Blocking experiments with anti-ICOS-L MoAb resulted in a significant inhibition of tT(Reg) cell generation whereas both IL-10 & TGFβ blockade did not. MM tumour cells can directly generate functional T(Reg) cells in a contact-dependent manner, mediated by ICOS/ICOS-L. These features suggest that tumour generation of T(Reg) cells may contribute to evasion of immune surveillance by the host.
Transplant Immunology Group, Academic Department of Haematology and Oncology, University of Leeds, Leeds, United Kingdom.
Sylvia
S
Feyler
Gina B
GB
Scott
Christopher
C
Parrish
Sarah
S
Jarmin
Paul
P
Evans
Mike
M
Short
Katherine
K
McKinley
Peter J
PJ
Selby
Gordon
G
Cook
D000938:Antigen-Presenting Cells / Q000276:immunology; D002450:Cell Communication / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D010950:Plasma Cells / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
C556692:ICOS protein, human; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma