Search

A tumour microenvironment abundant in regulatory T (Treg) cells aids solid tumours to evade clearance by effector T cells. Systemic strategies to suppress Treg cells or to augment immunity can elicit autoimmune side effects, cytokine storms and other toxicities. Here we report the design, fabrication and therapeutic performance of a biodegradable macroporous scaffold, implanted peritumourally, that releases a small-molecule inhibitor of transforming growth factor β to suppress Treg cells, chemokines to attract effector T cells and antibodies to stimulate them. In two mouse models of aggressive tumours, the implant boosted the recruitment and activation of effector T cells into the tumour and depleted it of Treg cells, which resulted in an 'immunological abscopal effect' on distant metastases and in the establishment of long-term memory that impeded tumour recurrence. We also show that the scaffold can be used to deliver tumour-antigen-specific T cells into the tumour. Peritumourally implanted immunomodulatory scaffolds may represent a general strategy to enhance T-cell immunity and avoid the toxicities of systemic therapies.

Recent innovations in immunoregulatory treatments have demonstrated both the impressive potential and vital role of T cells in fighting cancer. These treatments come at a cost, with systemic side effects including life-threatening autoimmunity and immune dysregulation the norm. Here, we developed an approach to locally synthesize immune therapies and in this way, avoid systemic toxicity. Rather than just encapsulating cytokines, we endowed our nanoparticles with transcriptional and translational machinery to make cytokines locally, in situ, and on demand (activated by light). We demonstrated the capabilities of these particles in vitro and in vivo, in a mouse model of melanoma, and showed that tumor-infiltrating T cells were more highly activated in the context of these "microfactory" particles that make the synthetic cytokine.

T cells recognize mechanical forces through a variety of cellular pathways, including mechanical triggering of both the T-cell receptor (TCR) and integrin LFA-1. Here we show that T cells can recognize forces arising from the mechanical rigidity of the microenvironment. We fabricated 3D scaffold matrices with mechanical stiffness tuned to the range 4-40 kPa and engineered them to be microporous, independently of stiffness. We cultured T cells and antigen presenting cells within the matrices and studied T-cell activation by flow cytometry and live-cell imaging. We found that there was an augmentation of T-cell activation, proliferation, and migration speed in the context of mechanically stiffer 3D matrices as compared to softer materials. These results show that T cells can sense their 3D mechanical environment and alter both their potential for activation and their effector responses in different mechanical environments. A 3D scaffold of tunable stiffness and consistent microporosity offers a biomaterial advancement for both translational applications and reductionist studies on the impact of tissue microenvironmental factors on cellular behavior.

Upon immunogenic challenge, lymph nodes become mechanically stiff as immune cells activate and proliferate within their encapsulated environments, and with resolution, they reestablish a soft baseline state. Here we show that sensing these mechanical changes in the microenvironment requires the mechanosensor YAP. YAP is induced upon activation and suppresses metabolic reprogramming of effector T cells. Unlike in other cell types in which YAP promotes proliferation, YAP in T cells suppresses proliferation in a stiffness-dependent manner by directly restricting the translocation of NFAT1 into the nucleus. YAP slows T cell responses in systemic viral infections and retards effector T cells in autoimmune diabetes. Our work reveals a paradigm whereby tissue mechanics fine-tune adaptive immune responses in health and disease.

Activation of T cells by antigen presenting cells (APCs) initiates their proliferation, cytokine production, and killing of infected or cancerous cells. We and others have shown that T-cell receptors require mechanical forces for triggering, and these forces arise during the interaction of T cells with APCs. Efficient activation of T cells in vitro is necessary for clinical applications. In this paper, we studied the impact of combining mechanical, oscillatory movements provided by an orbital shaker with soft, biocompatible, artificial APCs (aAPCs) of various sizes and amounts of antigen. We showed that these aAPCs allow for testing the strength of signal delivered to T cells, and enabled us to confirm that that absolute amounts of antigen engaged by the T cell are more important for activation than the density of antigen. We also found that when our aAPCs interact with T cells in the context of an oscillatory mechanoenvironment, they roughly double antigenic signal strength, compared to conventional, static culture. Combining these effects, our aAPCs significantly outperformed the commonly used Dynabeads. We finally demonstrated that tuning the signal strength down to a submaximal "sweet spot" allows for robust expansion of induced regulatory T cells. In conclusion, augmenting engineered aAPCs with mechanical forces offers a novel approach for tuning of T-cell activation and differentiation.

T-cell immunotherapy is a promising approach for cancer, infection, and autoimmune diseases. However, significant challenges hamper its therapeutic potential, including insufficient activation, delivery, and clonal expansion of T-cells into the tumor environment. To facilitate T-cell activation and differentiation in vitro, core-shell microparticles are developed for sustained delivery of cytokines. These particles are enriched by heparin to enable a steady release of interleukin-2 (IL-2), the major T-cell growth factor, over 10+ d. The controlled delivery of cytokines is used to steer lineage specification of cultured T-cells. This approach enables differentiation of T-cells into central memory and effector memory subsets. It is shown that the sustained release of stromal cell-derived factor 1α could accelerate T-cell migration. It is demonstrated that CD4+ T-cells could be induced to high concentrations of regulatory T-cells through controlled release of IL-2 and transforming growth factor beta. It is found that CD8+ T-cells that received IL-2 from microparticles are more likely to gain effector functions as compared with traditional administration of IL-2. Culture of T-cells within 3D scaffolds that contain IL-2-secreting microparticles enhances proliferation as compared with traditional, 2D approaches. This yield a new method to control the fate of T-cells and ultimately to new strategies for immune therapy.

This study is concerned with electrochemical investigation of novel high-performance proton exchange membranes based on bio-functionalized montmorillonite and Nafion®. It was found that the incorporation of 2 wt% BMMT into Nafion® polyelectrolyte matrix results in significantly improved methanol–air fuel cell efficiency of 30% compared to 14% for Nafion®117, and about 23-times higher membrane selectivity. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel proton exchange membranes based on Nafion® and 2-acrylamido-2-methylpropanesulfonic acid (AMPS) modified montmorillonite (MMT) were prepared and investigated for high performance fuel cell applications. X-ray diffraction patterns revealed an exfoliated microstructure for the modified clay in the Nafion® matrices. Proton conductivity and methanol permeability results indicated that the incorporation of AMPS-modified MMT into Nafion® matrices results in considerably reduced methanol crossover while maintaining conductivity properties. Direct methanol–air single fuel cell tests revealed a cell efficiency of 20% for Nafion®/AMPS-MMT-3wt.% compared to 13.72% for Nafion®117 at 5M methanol feed, and also a higher power density of 88mWcm−2 compared to 39mWcm−2 for Nafion®117. Owing to such favorable features, fabricated Nafion®/AMPS-MMT membranes could be considered as promising polymeric electrolytes for high performance fuel cell applications. [ABSTRACT FROM AUTHOR]

Abstract: Polyelectrolyte membranes based on Nafion® and bio-functionalized montmorillonite (BMMT) with chitosan biopolymer, as polycationic intercalant were fabricated by solvent casting method. X-ray diffraction analysis confirmed the exfoliated structure of clay. Methanol permeability results revealed that the presence of 10wt% BMMT in synthesized nanohybrid membranes can reduce the permeability to 5.72×10−8 cm2 s−1 in comparison with 2.00×10−6 for that of Nafion® 117. However proton conductivity of nanohybrids was decreasing with increasing BMMT loading, but obtained values were indicating the lower sacrificing of conductivity in comparison with membranes based on unmodified MMT. According to selectivity parameter, membranes containing 2wt% of BMMT showed optimum properties. It was suggested that improvement of transportation properties could be due to the electrostatic interaction between amino groups of chitosan and Nafion® sulfone groups. Considering the suitable thermal stability, low methanol crossover and appropriate proton conductivity properties, Nafion®/BMMT nanohybrid membranes, could be proposed as novel polyelectrolytes for direct methanol fuel cell application. [Copyright &y& Elsevier]