Journal
HUMAN VACCINES & IMMUNOTHERAPEUTICS
Volume 14, Issue 6, Pages 1423-1431Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/21645515.2018.1431598
Keywords
cholangiocarcinoma (CCA); dendritic cell (DC); immunosuppressive cytokines; IL-10 receptor (IL-10R); TGF- receptor (TGF-R)
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Funding
- International Research Network (IRN), Thailand Research Fund (TRF) [IRN58W0001, IRG5980006]
- TRF-Royal Golden Jubilee (RGJ)-Ph.D. Scholarship [PHD/0044/2556]
- TRF [TRG5780173]
- Siriraj Charoemprakiat Grant
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Tumor escapes host immune responses by producing immunosuppressive cytokines, such as IL-10 and TGF-, secreted into the tumor microenvironment. These cytokines play important roles in the suppression of dendritic cell (DC) function, leading to decreased immune responses of the effector CD4(+) and CD8(+) T cells. To improve DC functions and enhance cytolytic activity of activated effector T-cells, we suppressed the effect of these cytokines on DCs by using specific neutralizing antibodies that inhibit IL-10 and TGF- receptors. Monocyte-derived DCs generated in vitro showed up-regulation of MHC (HLA-DR) and co-stimulatory molecules (CD40 and CD86). The IL-10 and TGF- receptors were expressed and localized on cell membrane of DCs, as shown by Western blot analysis and immunofluorescence staining, whereas the IL-10 and TGF- ligands were detected in the culture supernatants of DCs and cholangiocarcinoma (CCA) cell line, respectively. Inhibition of the IL-10 and TGF- receptors on DCs by specific neutralizing antibodies significantly increased level of IFN- and enhanced cytolytic activity of the DC-activated effector T-cells against CCA cell line. These results indicate that the IL-10 and TGF- receptors are the targets for inhibition to increase DC functions and enhance cytolytic activity of the DC-activated effector T-cells against CCA cells. Thus, inhibition of the IL-10 and TGF- receptors on DCs is crucial in the preparation of DC-activated effector T cells for adoptive T-cell therapy.
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