Abstract
Microbial agents are regarded as a potential cause of tumors, but their direct effects on tumors, such as myeloma, are not well studied. Our studies demonstrated that expression of HLA-DR and CD40 on the myeloma cell membrane surface is upregulated by interferon-γ and/or microbial antigens (Ags). Unlike prior studies, our study showed that Th2 cells cannot promote myeloma growth directly. However, Bacillus Calmette–Guerin Vaccine (BCGV)-specific Th2 cells stimulated by BCGV-loaded dendritic cells (DCs) promoted myeloma clonogenicity directly when the myeloma cells expressed major histocompatibility complex Class-II molecules (MHC-II) and took up BCGV Ag. B-cell lymphoma 6 (Bcl-6) protein expression and the proportion of HLA-DR+ or CD40+ cells were higher in colonies of Th2 cell-stimulated myeloma cells. Furthermore, anti-HLA-DR or neutralizing CD40 antibody could prevent this increase in Bcl-6 expression and colony number. These results indicate that microbes and microbial Ag-specific Th2 cells may directly impact the biology of myeloma and contribute to tumor progression. Activation may be limited to MHC-II+ myeloma cells that retain B cell and stem cell characteristics. Taken together, our data suggest that factors involved in microbial Ag presentation, such as DCs, Th2 cells and so on, are potential targets for myeloma therapeutic intervention.
Highlights
Th2 cells are an important subset of antigen (Ag)-specific T cells.Several studies suggest that Th2 activation by tumor Ags may be a risk factor for multiple myeloma (MM).[1,2] Prior research has shown that the Th2 response can promote MM progression after idiotype-based immunotherapy.[3]
Treatment with IFN-g for 48 h markedly increased surface expression of HLA-DR, CD40 and CD80, but CD40 and CD80 expression were at a low levels, and CD86 and CD54 remained at a high level (Figure 1a)
Bacillus Calmette–Guerin Vaccine (BCGV)-Th2 cells had no impact on the clonogenicity of untreated-U266 cells and K562 cells and U266 treated by IFN-g alone (Figures 2b, d and g), and non-BCGV-specific Th2 cells and BCGV-specific CD8 þ T cells had
Summary
Th2 cells are an important subset of antigen (Ag)-specific T cells.Several studies suggest that Th2 activation by tumor Ags may be a risk factor for multiple myeloma (MM).[1,2] Prior research has shown that the Th2 response can promote MM progression after idiotype-based immunotherapy.[3]. Dendritic cells (DCs) are the most efficient Ag presenting cells (APCs) and can be used in Ag-based immunotherapy to activate all T-cell subsets.[3,4] When naıve T cells are stimulated by a Th2inducing Ag, they acquire the ability to interact with B cells that have taken up Ag.[5,6] Interaction of DCs with B cells may affect B-cell survival.[6,7] Prior studies have shown a correlation between increased infiltration of human tumors by DCs and adverse prognosis.[8,9,10] it has been demonstrated in vitro that interaction with DCs can directly enhance clonogenicity of human MM.[11] Considering that MM is a B-cell malignancy and Th2 cell–B-cell interaction is crucial for regulating B-cell function, we supposed that Ag-specific Th2 cells induced by DCs would promote the survival and growth of myeloma cells that express MHC-II molecules and take up the same Ag
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