Androgen receptor activity in T cells limits checkpoint blockade efficacy.

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.

Fertilization regimes affecting nickel phytomining efficiency on a serpentine soil in the temperate climate zone.

Phytomining of nickel (Ni) refers to cropping of selected Ni hyperaccumulator plants on Ni-rich serpentine soils. In this study, the effect of different fertilization regimes on the Ni yield of Odontarrhena chalcidica (syn. Alyssum murale) was evaluated within a field experiment on an Austrian serpentine site. Odontarrhena chalcidica was planted in six treatments: control, fertilized by mineral fertilizer, cow manure, pig manure, compost, and planted at higher plant density. A positive fertilization effect was observed: plants treated with NPK and pig manure produced significantly higher biomass (1.9 t ha-1 for both treatments). Nickel yields showed a clear trend for enhancement upon fertilization (cow manure: 22.7 kg Ni ha-1, pig manure: 21.3 kg Ni ha-1, NPK: 20.6 kg Ni ha-1), but were not significantly different from the control. As a result of Ni accumulation in plants, DTPA-extractable Ni pools were significantly lower after harvesting (average 37.3 mg kg Ni-DTPA-1) compared to the time of planting (average 45.6 mg kg Ni-DTPA-1) in organic fertilization treatments and plots of higher plant density. The application of organic fertilizers contributed also to improved soil quality. We conclude that fertilization can increase the phytomining potential of field-grown Ni hyperaccumulator plants in a soil-friendly manner.

A nickel phytomining field trial using Odontarrhena chalcidica and Noccaea goesingensis on an Austrian serpentine soil.

Phytomining of nickel (Ni) is based on the cropping of Ni hyperaccumulators on Ni-rich serpentine soils. The efficiency of this approach is dependent on shoot nickel concentration and harvestable biomass. In a field experiment conducted on an Austrian serpentine site, the phytomining efficiency of the two plant species Odontarrhena chalcidica (syn. Alyssum murale) and Noccaea goesingensis was evaluated. O. chalcidica was planted in three treatments: control, sulphur application (0.46 g S kg-1 soil) and intercropping with the legume Lotus corniculatus. For N. goesingensis the treatments control, high-density planting (110 plants m-2) and intercropping were implemented. Given the experimental set-up, shoot biomass, shoot Ni concentration and thus the total amount of harvested Ni were on average higher for O. chalcidica. The highest Ni yield was achieved with O. chalcidica, reaching 55 kg Ni ha-1 in the sulphur treatment. N. goesingensis showed the maximum yield in the high-density treatment with 36 kg Ni ha-1. However, high-density planting of N. goesingensis and sulphur application to O. chalcidica plots did not significantly increase the Ni yield compared to the control. Intercropping with L. corniculatus tended to decrease the shoot biomass of both species. Planting of the hyperaccumulators led to a decrease of DTPA-extractable Ni and to an increase of soil pH, with the exception of sulphur-amended plots. Likewise, rhizosphere soil pH was higher than bulk soil values. Our data suggest that in particular O. chalcidica is suitable for Ni phytomining on the tested site. Measures to further increase the Ni yield and to optimise crop management will be evaluated in follow-up experiments.

3D Printing of Microgel-Loaded Modular Microcages as Instructive Scaffolds for Tissue Engineering.

Biomaterial scaffolds have served as the foundation of tissue engineering and regenerative medicine. However, scaffold systems are often difficult to scale in size or shape in order to fit defect-specific dimensions, and thus provide only limited spatiotemporal control of therapeutic delivery and host tissue responses. Here, a lithography-based 3D printing strategy is used to fabricate a novel miniaturized modular microcage scaffold system, which can be assembled and scaled manually with ease. Scalability is based on an intuitive concept of stacking modules, like conventional toy interlocking plastic blocks, allowing for literally thousands of potential geometric configurations, and without the need for specialized equipment. Moreover, the modular hollow-microcage design allows each unit to be loaded with biologic cargo of different compositions, thus enabling controllable and easy patterning of therapeutics within the material in 3D. In summary, the concept of miniaturized microcage designs with such straight-forward assembly and scalability, as well as controllable loading properties, is a flexible platform that can be extended to a wide range of materials for improved biological performance.

MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling.

MicroRNAs (miRs) contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic signaling that is buffered by a miR. We demonstrate that genotoxic stress-induced miR-494 inhibits the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Gain- and loss-of-function experiments show that miR-494 exacerbates DNA damage and drives endothelial senescence. Increase of miR-494 affects telomerase activity, activates p21, decreases pRb pathways, and diminishes angiogenic sprouting. Genetic and pharmacological disruption of the MRN pathway decreases VEGF signaling, phenocopies miR-494-induced senescence, and disrupts angiogenic sprouting. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment.

Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation.