Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression

The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy

Influence of Landscape Structure and Human Modifications on Insect Biomass and Bat Foraging Activity in an Urban Landscape

Urban landscapes are often located in biologically diverse, productive regions. As such, urbanization may have dramatic consequences for this diversity, largely due to changes in the structure and function of urban communities. We examined the influence of landscape productivity (indexed by geology), housing density and vegetation clearing on the spatial distribution of nocturnal insect biomass and the foraging activity of insectivorous bats in the urban landscape of Sydney, Australia. Nocturnal insect biomass (g) and bat foraging activity were sampled from 113 sites representing backyard, open space, bushland and riparian landscape elements, across urban, suburban and vegetated landscapes within 60 km of Sydney's Central Business District. We found that insect biomass was at least an order of magnitude greater within suburban landscapes in bushland and backyard elements located on the most fertile shale influenced geologies (both p<0.001) compared to nutrient poor sandstone landscapes. Similarly, the feeding activity of bats was greatest in bushland, and riparian elements within suburbs on fertile geologies (p = 0.039). Regression tree analysis indicated that the same three variables explained the major proportion of the variation in insect biomass and bat foraging activity. These were ambient temperature (positive), housing density (negative) and the percent of fertile shale geologies (positive) in the landscape; however variation in insect biomass did not directly explain bat foraging activity. We suggest that prey may be unavailable to bats in highly urbanized areas if these areas are avoided by many species, suggesting that reduced feeding activity may reflect under-use of urban habitats by bats. Restoration activities to improve ecological function and maintain the activity of a diversity of bat species should focus on maintaining and restoring bushland and riparian habitat, particularly in areas with fertile geology as these were key bat foraging habitats

Shedding Light on The Role of Keratinocyte-Derived Extracellular Vesicles on Skin-Homing Cells

Extracellular vesicles (EVs) are secretory lipid membranes with the ability to regulate cellular functions by exchanging biological components between different cells. Resident skin cells such as keratinocytes, fibroblasts, melanocytes, and inflammatory cells can secrete different types of EVs depending on their biological state. These vesicles can influence the physiological properties and pathological processes of skin, such as pigmentation, cutaneous immunity, and wound healing. Since keratinocytes constitute the majority of skin cells, secreted EVs from these cells may alter the pathophysiological behavior of other skin cells. This paper reviews the contents of keratinocyte-derived EVs and their impact on fibroblasts, melanocytes, and immune cells to provide an insight for better understanding of the pathophysiological mechanisms of skin disorders and their use in related therapeutic approaches