Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation

Therapeutic vaccination with dendritic cells (DC) is an emerging investigational therapy for eradication of minimal residual disease in acute myeloid leukemia. Various strategies are being explored in manufacturing DC vaccines ex vivo, e.g., monocyte-derived DC (MoDC) loaded with leukemia-associated antigens (LAA). However, the optimal source of LAA and the choice of DC-activating stimuli are still not well defined. Here, loading with leukemic cell preparations (harboring both unknown and known LAA) was explored in combination with a DC maturation-inducing cytokine cocktail (CC; IL-1β, IL-6, TNF-α, and PGE2) and Toll-like receptor ligands (TLR-L) to optimize uptake. Since heat shock induced apoptotic blasts were more efficiently taken up than lysates, we focused on uptake of apoptotic leukemic cells. Uptake of apoptotic blast was further enhanced by the TLR7/8-L R848 (20–30%); in contrast, CC-induced maturation inhibited uptake. CC, and to a lesser extent R848, enhanced the ability of MoDC to migrate and stimulate T cells. Furthermore, class II-associated invariant chain peptide expression was down-modulated after R848- or CC-induced maturation, indicating enhanced processing and presentation of antigenic peptides. To improve both uptake and maturation, leukemic cells and MoDC were co-incubated with R848 for 24 h followed by addition of CC. However, this approach interfered with CC-mediated MoDC maturation as indicated by diminished migratory and T cell stimulatory capacity, and the absence of IL-12 production. Taken together, our data demonstrate that even though R848 improved uptake of apoptotic leukemic cells, the sequential use of R848 and CC is counter-indicated due to its adverse effects on MoDC maturation

Manipulating thermal fields with inhomogeneous heat spreaders

We design a class of spatially inhomogeneous heat spreaders in the context of steady-state thermal conduction leading to spatially uniform thermal fields across a large convective surface. Each spreader has a funnel-shaped design, either in the form of a trapezoidal prism or truncated cone, and is forced by a thermal source at its base. We employ transformation-based techniques, commonly used to study metamaterials, to determine the require thermal conductivity for the spreaders. The obtained materials, although strongly anisotropic and inhomogeneous, can be accurately approximated by assembling isotropic, homogeneous layers, rendering them realisable. An alternative approach is then considered for the conical and trapezoidal spreaders by dividing them into two or three isotropic, homogeneous components respectively. We refer to these simple configurations as neutral layers. All designs are validated numerically both with and without the effects of thermal contact resistance between interfaces. Such novel designs pave the way for future materials that can manipulate and control the flow of heat, helping to solve traditional heat transfer problems such as controlling the temperature of an object and energy harvesting