Immunoregulation of Dendritic Cell Subsets by Inhibitory Receptors in Urothelial Cancer.

Blockade of inhibitory receptors (IRs) overexpressed by T cells can activate antitumor immune responses, resulting in the most promising therapeutic approaches, particularly in bladder cancer, currently able to extend patient survival. Thanks to their ability to cross-present antigens to T cells, dendritic cells (DCs) are an immune cell population that plays a central role in the generation of effective antitumor T-cell responses. While IR function and expression have been investigated in T cells, very few data are available for DCs. Therefore, we analyzed whether DCs express IRs that can decrease their functions. To this end, we investigated several IRs (PD-1, CTLA-4, BTLA, TIM-3, and CD160) in circulating CD1c javax.xml.bind.JAXBElement@4f1331d4 DCs, CD141 javax.xml.bind.JAXBElement@68e4feef DCs, and plasmacytoid DCs from healthy donors and patients with urothelial cancer (UCa). Different DC subsets expressed BTLA and TIM-3 but not other IRs. More importantly, BTLA and TIM-3 were significantly upregulated in DCs from blood of UCa patients. Locally, bladder tumor-infiltrating DCs also overexpressed BTLA and TIM-3 compared to DCs from paired nontumoral tissue. Finally, in vitro functional experiments showed that ligand-mediated engagement of BTLA and TIM-3 receptors significantly reduced the secretion of effector cytokines by DC subpopulations. Our findings demonstrate that UCa induces local and systemic overexpression of BTLA and TIM-3 by DCs that may result in their functional inhibition, highlighting these receptors as potential targets for UCa treatment. We investigated the expression and function of a panel of inhibitory receptors in dendritic cells (DCs), an immune cell subpopulation critical in initiation of protective immune responses, among patients with urothelial carcinoma. We found high expression of BTLA and TIM-3 by blood and tumor DCs, which could potentially mediate decreased DC function. The results suggest that BTLA and TIM-3 might be new targets for urothelial carcinoma treatment

Detection of functional antigen-specific T cells from urine of non-muscle invasive bladder cancer patients.

To gain further insights into the role of T lymphocytes in immune responses against bladder tumors, we developed a method that monitors the presence of functional antigen-specific T cells in the urine of non-muscle invasive bladder cancer patients. As relatively few immune cells can usually be recovered from urine, we examined different isolation/amplification protocols and took advantage of patients treated with weekly intravesical instillations of Bacillus Calmette-Guérin, resulting in large amounts of immune cells into urine. Our findings demonstrate that, upon in vitro amplification, antigen-specific T cells can be detected by an interferon γ (IFNγ)-specific ELISPOT assay

Ultrahigh-density trench cpacitors in silicon and their application to integrated DC-DC conversion

This paper addresses silicon-based integration of passive components applied to 3D integration with dies of other technologies within one package. Particularly, the development of high-density trench capacitors has enabled the realization of small-formfactor DC-DC converters. As illustration, an integrated inductive DC-DC converter based on flip-chipping a 65-nm CMOS active die on a PICSÔ (Passive-Integration Connecting Substrate) passive die is described. The PICS die includes high-density (80 nF/mm2) integrated MOS trench capacitors. A converter peak efficiency of 87.5% is achieved at Vin=1.2 V, Vout=0.95 V, Iout=100 mA and 100-MHz switching frequency. The concept enables further integration with sensors, actuators and MEMS

Ultrahigh-density trench cpacitors in silicon and their application to integrated DC-DC conversion

This paper addresses silicon-based integration of passive components applied to 3D integration with dies of other technologies within one package. Particularly, the development of high-density trench capacitors has enabled the realization of small-formfactor DC-DC converters. As illustration, an integrated inductive DC-DC converter based on flip-chipping a 65-nm CMOS active die on a PICSÔ (Passive-Integration Connecting Substrate) passive die is described. The PICS die includes high-density (80 nF/mm2) integrated MOS trench capacitors. A converter peak efficiency of 87.5% is achieved at Vin=1.2 V, Vout=0.95 V, Iout=100 mA and 100-MHz switching frequency. The concept enables further integration with sensors, actuators and MEMS