Tumor-derived CD4+CD25+regulatory T cells inhibit dendritic cells function by CTLA-4.

CD4+CD25+regulatoryT cells (Tregs) play an important role in anti-tumor immune responses. Poor prognosis and declining survival rates have intimate connection with high Treg expression in cancer patients. Cytotoxic T Lymphocyte-associated protein (CTLA-4) is one of the most prominent molecules on Treg. In our previous research, we have demonstrated that HCC-derived Tregs can interfere with Dendritic cells (DCs) function and down-modulate CD80/CD86 on DCs in vitro in a cell-contact dependent way. However the mechanism of how HCC-derived Treg affect DC phenotype are not very clear. Therefore, we investigated the function of CTLA-4 in anti-tumor immune responses. We established BABL/C mouse with hepatocellular carcinoma model, and tumor-derived Tregs were purified by magnetic cell sorting using mouse CD4+CD25+regulatoryT cell isolation kit. Splenic DCs were enriched using CD11c-conjugated microbeads. Then splenic DCs co-cultured with tumor-derived Tregs and antibody-blocking experiments was performed. In our research, we found the down-modulation of CD80/CD86 on DCs was inhibited by blocking CTLA-4. HCC-derived Tregs down-modulated CD80/CD86 on DCs in a CTLA-4-dependent way. Blockade of CTLA-4 can lead to increase DC-mediated immunity. CTLA-4 play a vital role in Treg-mediated immnue inhibition and this discovery can open up new ideas for the development of therapeutic strategies.

Chen X ，Du Y ，Hu Q ，Huang Z ... -  《-》

CD4+CD25+ Treg derived from hepatocellular carcinoma mice inhibits tumor immunity.

CD4+CD25+ regulatory T cells (Tregs) play an essential role in the establishment and persistence of tumor immune suppression. Tregs can prevent anti-tumor-specific T cells from clearing the tumor, making Tregs a significant barrier for effective immunotherapy. An increase in the number of Tregs has been detected in the peripheral blood and tumor infiltrating lymphocytes of patients with hepatocellular carcinoma. Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in the initiation of immune responses. The evidence for their ability to act as natural adjuvant in the stimulation of specific anti-tumor cytotoxic T lymphocytes and in the induction of protective and therapeutic anti-tumor immunity is now overwhelming. The aim of our study was to investigate the variation of Tregs in hepatocellular carcinoma mice and how Tregs derived from the tumor mice affect DCs' function. We found that Tregs derived from the tumor mice down-regulated the expression of costimulatory molecules CD80/CD86 on DCs and inhibited the production of TNF-α and IL-12 from DCs. The suppressive function of Tregs was mediated by cell-to-cell contact, CTLA-4 expression and IL-10 secretion. In conclusion, these mechanisms acting in hepatocellular carcinoma may be necessary to better understand the immunosuppression of Tregs and helpful to the tumor immunotherapy.

Chen X ，Du Y ，Huang Z 《-》

Tolerogenic dendritic cells suppress murine corneal allograft rejection by modulating CD28/CTLA-4 expression on regulatory T cells.

Anterior chamber-associated immune deviation (ACAID) is initiated when dendritic cells (DCs) capture intraocular antigen and induce regulatory T cells (Tregs) in the spleen. We investigated whether DCs could be used as an immunotherapy to prevent murine corneal allograft rejection by inducing Tregs. Bone marrow-derived DCs (BMDCs) were differentiated with transforming growth factor-β2 (TGF-β2) in the presence of donor-derived allopeptide in vitro (TGFβ2-DCs), and adoptively transferred to BALB/c mice. Three days later a corneal allograft transplant was carried out. Graft rejection, as well as the number and the phenotype of splenic Tregs, were determined after transplant. CD86, CD80, CD40 were present, and MHC class II expression were significantly reduced on TGFβ2-DCs compared to BMDCs not exposed to TGF-β2. TGFβ2-DCs increased the number of splenic Tregs (CD4(+)CD25(+)) in recipient mice prior to transplant by modulating CD28/CTLA-4 expression. These induced Tregs suppressed proliferation of CD4(+)CD25(-) T cells ex vivo. TGFβ2-DCs delayed corneal allograft rejection and TGFβ2-DC recipient mice had significantly more splenic Tregs expressing Foxp3 and CTLA-4, but fewer CD28+ Tregs. Expression of GITR, CD69, and CD45RB were similar in TGFβ2-DC and control mice. Therefore, the phenotype of TGFβ2-DCs suggests they are tolerogenic DCs (tolDCs). In vivo, these cells increased the number and function of Tregs by modulating CD28/CTLA-4 expression. The suppressor Tregs induced by TGFβ2-DCs may be involved in the induction of ACAID, which helps to suppress corneal allograft rejection. Our results provide proof of principle for the use of tolDCs as immunotherapy during transplant.

Yan F ，Cai L ，Hui Y ，Chen S ，Meng H ，Huang Z ... -  《-》

Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells.

Tekguc M ，Wing JB ，Osaki M ，Long J ，Sakaguchi S ... -  《-》

Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. HCC-induced immunosuppression often leads to ineffectiveness of immuno-promoting therapies. Currently, suppressing the suppressors has become the potential strategy for cancer immunotherapy. So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy. Here, we identified one new subset of human CD14(+) CTLA-4(+) regulatory dendritic cells (CD14(+) DCs) in HCC patients, representing ∼13% of peripheral blood mononuclear cells. CD14(+) DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14(+) DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression. These data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14(+) DCs, which may contribute to HCC progression. This adds new insight to the mechanism for HCC-induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC.

Han Y ，Chen Z ，Yang Y ，Jiang Z ，Gu Y ，Liu Y ，Lin C ，Pan Z ，Yu Y ，Jiang M ，Zhou W ，Cao X ... -  《-》