Yun-Sun Kim

A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model

Her-2/neu is a well-characterized tumor-associated antigen overexpressed in human carcinomas such as breast cancer. Because Her-2/neu is a self-antigen with poor immunogenicity due to immunologic tolerance, active immunotherapy targeting Her-2/neu should incorporate methods to overcome immunologic tolerance to self-proteins. In this study, we developed a tolerogenic tumor model in mice using mouse Her-2/neu as self-antigen and investigated whether genetic vaccination with DNA plasmid and/or adenoviral vector expressing the extracellular and transmembrane domain of syngeneic mouse Her-2/neu or xenogenic human Her-2/neu could induce mouse Her-2/neu-specific CTL responses. Interestingly, adenoviral vectors expressing xenogenic human Her-2/neu (AdhHM) proved capable of breaking immune tolerance and of thereby inducing self-reactive CTL and antibodies, but not to the degree required to induce therapeutic antitumor immunity. In attempting to generate therapeutic antitumor immunity against established tumors, we adopted several approaches. Treatment with agonistic anti-glucocorticoid-induced TNFR family-related receptor (GITR) antibody plus AdhHM immunization significantly increased self-reactive CTL responses, and alpha-galactosylceramide (alphaGalCer)-loaded dendritic cells (DC) transduced with AdhHM were shown to break self-tolerance in a tolerogenic murine tumor model. Furthermore, gemcitabine treatment together with either AdhHM plus agonistic anti-GITR antibody administration or alphaGalCer-loaded DC transduced with AdhHM showed potent therapeutic antitumor immunity and perfect protection against preexisting tumors. Gemcitabine treatment attenuated the tumor-suppressive environment by eliminating CD11b(+)/Gr-1(+) myeloid-derived suppressor cells. When combined with immunotherapies, gemcitabine offers a promising strategy for the Ag-specific treatment of human cancer.

Polarization Relaxation Induced by a Depolarization Field in Ultrathin Ferroelectric BaTiO~3 Capacitors

Time-dependent polarization relaxation behavior induced by a depolarization field E(d) was investigated on high-quality ultrathin SrRuO3/BaTiO3/SrRuO3 capacitors. The E(d) values were determined experimentally from an applied external field to stop the net polarization relaxation. These values agree with those from the electrostatic calculations, demonstrating that a large E(d) inside the ultrathin ferroelectric layer could cause severe polarization relaxation. For numerous ferroelectric devices of capacitor configuration, this effect will set a stricter size limit than the critical thickness issue.

Cutting Edge: Programmed Death-1/Programmed Death Ligand 1 Interaction Regulates the Induction and Maintenance of Invariant NKT Cell Anergy

Invariant NKT (iNKT) cells are a distinct subset of T lymphocytes that recognize glycolipid Ags. Upon TCR stimulation, iNKT cells promptly secrete a wide range of cytokines and therefore have been investigated as a target for immunotherapy. However, after primary activation, iNKT cells become hyporesponsive toward their ligand (anergy). The further mechanism behind iNKT cell anergy is poorly understood. We found that a low level of programmed death-1 (PD-1) was constitutively expressed on iNKT cells and that PD-1 expression was increased after stimulation and lasted at least 2 mo. Moreover, not only did blocking of the PD-1/PD ligand 1 (PD-L1) pathway prevent the induction of anergy in iNKT cells, but anergic iNKT cells also recovered responsiveness and these “rescued” cells efficiently mediated antitumor immunity. Our findings suggest that the PD-1/PD-L1 interaction is essential for the induction and maintenance of iNKT cell anergy.

Immunosuppressive Myeloid-Derived Suppressor Cells Can Be Converted into Immunogenic APCs with the Help of Activated NKT Cells: An Alternative Cell-Based Antitumor Vaccine

Myeloid-derived suppressor cells (MDSCs), which are known to be accumulated in the blood, spleen, and bone marrow of tumor-bearing mice and cancer patients, were tested as APCs for a cellular vaccine because they have phenotypical similarity with inflammatory monocytes and may be differentiated from the same precursors as monocytes. Although MDSCs have immunosuppressive properties, in vivo transferred MDSCs, which present tumor Ag and NKT cell ligand (α-galactosylceramide), significantly prolonged survival time in metastatic tumor-bearing mice in a CD8+ cell-, NK cell-, and NKT cell-dependent manner vs a CD4+ T cell- and host dendritic cell-independent manner. Major concerns about using MDSCs as APCs in a vaccine are their suppression of CTLs and their induction of Foxp3+ regulatory T cells. However, α-galactosylceramide-loaded MDSCs did not suppress CD4+ and CD8+ T cells and allowed for the generation of Ag-specific CTL immunity without increasing the generation of regulatory T cells. Furthermore, stimulation with activated NKT cells induced changes on MDSCs in phenotypical or maturation markers, including CD11b, CD11c, and CD86. Taken together, these findings suggest that NKT cells facilitate the conversion of immunosuppressive MDSCs into immunogenic APCs, eliciting successful antitumor immunity and providing the basis for alternative cell-based vaccines.

Ferroelectric properties of SrRuO3∕BaTiO3∕SrRuO3 ultrathin film capacitors free from passive layers

Structural studies on ultrathin SrRuO3∕BaTiO3∕SrRuO3 capacitors, with BaTiO3 thicknesses of between 5nm and 30nm, show well-defined interfaces between ferroelectric BaTiO3 and electrode SrRuO3 layers. In these capacitors, we cannot observe any extrinsic electrical effects due to either the formation of an insulating interfacial passive layer or passive-layer-induced charge injection. Such high-quality interfaces result in very good fatigue endurance, even for the 5nm thick BaTiO3 capacitor.Structural studies on ultrathin SrRuO3∕BaTiO3∕SrRuO3 capacitors, with BaTiO3 thicknesses of between 5nm and 30nm, show well-defined interfaces between ferroelectric BaTiO3 and electrode SrRuO3 layers. In these capacitors, we cannot observe any extrinsic electrical effects due to either the formation of an insulating interfacial passive layer or passive-layer-induced charge injection. Such high-quality interfaces result in very good fatigue endurance, even for the 5nm thick BaTiO3 capacitor.

The restoration of myeloid-derived suppressor cells as functional antigen-presenting cells by NKT cell help and all-trans-retinoic acid treatment

Myeloid‐derived suppressor cells (MDSCs), which accumulate during tumor progression, have been shown to function as important suppressor cells. In a previous study, we showed that immunosuppressive MDSCs could function as immunogenic antigen‐presenting cells (APCs) with the help of activated natural killer T (NKT) cells. In the current study, however, we found that MDSCs harvested at a late time point after tumor injection (late MDSCs) were poorly immunogenic even when stimulated with activated NKT cells. As tumor growth progressed, the expression of MHC and costimulatory molecules on MDSCs was gradually down‐regulated. Late MDSCs also had innate defects in activation and differentiation mediated by cytokine stimuli. Although late MDSCs treated only with all‐trans‐retinoic acid (ATRA), a stimulating agent for MDSC differentiation, could not become immunogenic, NKT ligand‐loaded, ATRA‐treated late MDSCs could be converted into immunogenic APCs to induce incremental immune responses. Furthermore, these effects were mediated by NKT cells secreting IFNγ, and ATRA‐mediated increases in glutathione (GSH) levels. Thus, combined treatment with differentiating and activating agents is a prerequisite for the conversion of late MDSCs into immunogenic APCs. Collectively, these results suggest that combined treatments are required for the differentiation and activation of late MDSCs in late stage cancer.

Polarization Switching Dynamics Governed by the Thermodynamic Nucleation Process in Ultrathin Ferroelectric Films

In most ferroelectrics, the domain nucleation barrier (U*) is thermally insurmountable; this is called Landauers paradox. However, we showed that, in ultrathin films, the large depolarization fields could lower U* to a level comparable to thermal energy (k(B)T), resulting in power-law decay of polarization. We empirically found a universal relation between the power-law decay exponent and U*/k(B)T. This relation will provide a practical but fundamental limit for capacitor-type ferroelectric devices, analogous to the superparamagnetic limit for magnetic memory devices.

Coercive fields in ultrathin BaTiO3 capacitors

Thickness-dependence of coercive field (EC) was investigated in ultrathin BaTiO3 capacitors with thicknesses (d) between 30 and 5.0nm. The EC appears nearly independent of d below 15nm, and decreases slowly as d increases above 15nm. This behavior can be explained not by effects of interfacial passive layers or strain relaxation, but by domain nuclei formation models. Based on domain nuclei formation models, the observed EC behavior is explainable via a quantitative level. A crossover of domain shape from a half-prolate spheroid to a cylinder is also suggested at d∼15nm, exhibiting good agreement with experimental results.

Functional Changes in Myeloid-Derived Suppressor Cells (MDSCs) during Tumor Growth: FKBP51 Contributes to the Regulation of the Immunosuppressive Function of MDSCs

Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were downregulated but protumor function-related genes were upregulated in both monocytic MDSCs (Mo-MDSCs) and polymorphonuclear granulocytic MDSCs (PMN-MDSCs) at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo-MDSCs and PMN-MDSCs isolated from the late time points. Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs.

Conversion from unipolar to bipolar resistance switching by inserting Ta2O5 layer in Pt/TaOx/Pt cells

We observed unipolar resistance switching in Pt/TaOx/Pt cells. We could make the cell have the bipolar resistance switching by inserting a stoichiometric Ta2O5 layer between Pt and TaOx layers. Bipolar resistance switching in Pt/Ta2O5/TaOx/Pt cells occurred reliably without applying an external compliance current. With increase in the Ta2O5 layer thickness, the current value at the low-resistance state became decreased but the forming voltage became increased. We could explain these intriguing phenomena using the interface-modified random circuit breaker network model.