Inhibition of IL-10 and TGF-β receptors on dendritic cells enhances activation of effector T-cells to kill cholangiocarcinoma cells

Abstract

Tumor escapes host immune responses by producing immunosuppressive cytokines, such as IL-10 and TGF-β, 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-β 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-β 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-β ligands were detected in the culture supernatants of DCs and cholangiocarcinoma (CCA) cell line, respectively. Inhibition of the IL-10 and TGF-β receptors on DCs by specific neutralizing antibodies significantly increased level of IFN-γ and enhanced cytolytic activity of the DC-activated effector T-cells against CCA cell line. These results indicate that the IL-10 and TGF-β 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-β receptors on DCs is crucial in the preparation of DC-activated effector T cells for adoptive T-cell therapy.

Attenuation of CD47-SIRPα Signal in Cholangiocarcinoma Potentiates Tumor-Associated Macrophage-Mediated Phagocytosis and Suppresses Intrahepatic Metastasis

“…Elevations of CXCL5, IL-6, and IL-8 and their contributions to dismal prognosis of CCA were reported [15] , [17] , [44] . IL-6 and GROα from CCA-stimulated mesenchymal cells promoted CCA growth [45] , and IL-10 from CCA promoting CCA progression were shown [46] . The induction of MCP-2 in M-CSF–induced MDM has been reported [47] , and we showed higher MCP-2 in TAM-like MDM.…”

Treg Heterogeneity, Function, and Homeostasis

“…They can suppress the activation and proliferation of effector T and B lymphocytes; they can also directly induce pTregs and Bregs (75)(76)(77)(78). In addition, TGF-β and IL-10 inhibit antigenic presentation to stimulate the generation of tolerogenic dendritic cells, which in their turn enable pTreg induction (79)(80)(81)(82)(83). Note that two pTreg populations have been well-described: Th3 and Tr1, featuring high TGF-β, and IL-10 secretion, respectively.…”

TlR2 and TlR4 are involved in the treatment of rheumatoid arthritis synovial fibroblasts with a medicated serum of asarinin through inhibition of Th1/Th17 cytokines

“…It has become clear in the last few years that T cell-derived cytokines expressed preferentially by T h 1 cells contribute to joint destruction and inflammatory response in RA, whereas T h 2 cell-associated cytokines may be protective (2,3). However, recent research on T h 17 cells and regulatory T cells (Treg) has demonstrated that an imbalance between T h 1/T h 2/T h 17/Treg cells is important to the pathogenesis of RA (4)(5)(6). Although the origin of RA is unclear, it has been determined that lymphocytes accumulate around the terminal blood vessels of the subsynovial layer prior to the inflammatory response (7).…”