Artificial structures capable of replicating at least some of the functions of natural organs and tissues may turn out to be quite different in shape, structure, and content when compared to their natural counterparts. This is particularly true for chemical factory tissues, such as the liver, or tissues in which cells migrate and collaborate, such as lymph nodes. In today's research, scientists demonstrate that a comparatively simple structure can perform some of the same useful functions of a lymph node, at least those related to training and replicating T cells to attack a particular pathogen or cancer cell population.
Natural lymph nodes act as a point of coordination for the immune system, allowing cells to recognize threats and marshal in numbers to fight it. Unfortunately lymph nodes deteriorate and become fibrotic with age, and this degrades the immune response by preventing the necessary coordination between cells. It is a major concern for the many groups attempting to produce rejuvenation of the aged immune system in one way or another. It is interesting to consider that there may be shortcuts towards useful implanted structures in the near future, artificial constructs that are far removed from an actual tissue engineered replacement lymph node, but that nonetheless alleviate a part of this problem. The work here is a very early proof of concept carried out with the goal of replicating T cells more efficiently outside the body, but it could nonetheless be carried forward to potential use in implants.
n the past few years, a wave of discoveries has advanced new techniques to use T-cells - a type of white blood cell - in cancer treatment. To be successful, the cells must be primed, or taught, to spot and react to molecular flags that dot the surfaces of cancer cells. The job of educating T-cells this way typically happens in lymph nodes, small, bean-shaped glands found all over the body that house T-cells. But in patients with cancer and immune system disorders, that learning process is faulty, or doesn't happen.
CAR-T therapy generally takes about six to eight weeks to culture engineered T-cells in laboratories. To make the engineered T-cells' environment more biologically realistic, researchers tried using a jelly-like polymer, or hydrogel, as a platform for the T-cells. On the hydrogel, the scientists added two types of signals that stimulate and "teach" T-cells to hone in on foreign targets to destroy. In their experiments, T-cells activated on hydrogels produced 50 percent more molecules called cytokines, a marker of activation, than T-cells kept on plastic culture dishes.
Because hydrogels can be made to order, scientists created and tested a range of hydrogels, from the very soft feel of a single cell to the more rigid quality of a cell-packed lymph node. One of the surprising findings was that T-cells prefer a very soft environment, similar to interactions with individual cells, as opposed to a densely packed tissue. More than 80 percent of T-cells on the soft surface multiplied themselves, compared with none of the T-cells on the most firm type of hydrogel. "As we perfect the hydrogel and replicate the essential feature of the natural environment, including chemical growth factors that attract cancer-fighting T-cells and other signals, we will ultimately be able to design artificial lymph nodes for regenerative immunology-based therapy."
T cell therapies require the removal and culture of T cells ex vivo to expand several thousand-fold. However, these cells often lose the phenotype and cytotoxic functionality for mediating effective therapeutic responses. The extracellular matrix (ECM) has been used to preserve and augment cell phenotype; however, it has not been applied to cellular immunotherapies. Here, a hyaluronic acid (HA)-based hydrogel is engineered to present the two stimulatory signals required for T-cell activation - termed an artificial T-cell stimulating matrix (aTM).
It is found that biophysical properties of the aTM - stimulatory ligand density, stiffness, and ECM proteins - potentiate T cell signaling and skew phenotype of both murine and human T cells. Importantly, the combination of the ECM environment and mechanically sensitive TCR signaling from the aTM results in a rapid and robust expansion of rare, antigen-specific CD8+ T cells. Adoptive transfer of these tumor-specific cells significantly suppresses tumor growth and improves animal survival compared with T cells stimulated by traditional methods. Beyond immediate immunotherapeutic applications, demonstrating the environment influences the cellular therapeutic product delineates the importance of the ECM and provides a case study of how to engineer ECM-mimetic materials for therapeutic immune stimulation in the future.