γδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tumors (i.e. Vδ1 and Vδ2), are being developed. The Vδ1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vδ2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vγ9Vδ2 T-cells in the peripheral blood alone (1-10% of the total CD3+ T-cell population), which can rapidly expand upon stimulation. The Vγ9Vδ2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vγ9Vδ2 T-cells were based on either ex vivo expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally \mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vγ9Vδ2 T-cells in cancer immunotherapy. Here, we review γδ T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results.

For well-mixed estuaries, key physical mechanisms are identified and quantified that cause changes in characteristics of the semi-diurnal sea surface elevation and lateral velocity due to modifications of the lateral bottom profile, channel deepening, and sea level rise. This is done by decomposing solutions of a new analytical model into components relating to different physical processes. The default geometry and parameter values are representative for the Ems estuary, with a converging width and a reflective landward boundary. The default Gaussian lateral bottom profile is modified to obtain profiles with the same crosssectional area, but with a different skewness or steepness. Results show that a steeper lateral bottom profile leads to amplification of the sea surface elevation. The width convergence is shown to influence the resonance characteristics. Channel deepening and sea level rise result in amplification of the sea surface elevation until a resonance peak is reached. When flooding is incorporated, the amount of sea level rise at which maximum tidal amplification occurs is found to be about two times lower. When using a symmetric Gaussian bottom profile, the lateral tidal flow is determined by Coriolis deflection of longitudinal flow and lateral density gradients caused by differential salt advection. However, an additional lateral tidal flow component incorporating the effect of continuity related to sea level variations and longitudinal gradients in longitudinal flow is shown to become increasingly important for skewed lateral bottom profiles. Furthermore, the lateral flow due to the lateral density gradient is enhanced for bottom profiles with increased steepness.

A three‐dimensional analytical model was used to understand tidal dynamics in deep and narrow (fjord‐like) basins. This model allows the width of the basin to decay exponentially with along‐channel distance from the mouth. Both the length scale of exponential convergence Lb∗ and the friction parameter Av∗ (vertical eddy viscosity) were the free parameters. Model results show amplification of the tidal amplitude toward the head of the basin. Amplification depends on the narrowing rate of the funnel‐like width of the channel and on friction. Cross‐channel variations in along‐channel tidal flow are also sensitive to the friction parameter. A typical along‐channel tidal flow distribution was found across the channel when the vertical eddy viscosity was characteristic of a basin with strong friction, or the Stokes number was larger than 0.1 (St > 0.1). Maximum along‐channel tidal velocities (ranging from 0.25 to 0.5 m s−1 depending on width convergence strength) were located in the center of the basin and at the surface. Decreasing values of the Stokes number, St < 0.1, resulted in along‐channel velocity maxima located near the lateral boundaries and subsurface in the middle of the channel. These tidal flow distributions were explained by a critical value of St and were verified with observations from Reloncavi Fjord, Chilean Patagonia yielding good agreement.