Journal club: fighting disease

Even though we are constantly surrounded by disease-inducing particles, most of us are healthy most of the time. We owe this to our immune system, which can combat most diseases that we are faced with. Fighting disease is based on our immune system’s amazing ability to distinguish ‘self’ from ‘non-self’. It is because of this ability that immune cells generally do not combat our own cells, but immediately start immune responses once non-self particles are recognized. The specific immune response that is started depends on the type of immune cell and the particle encountered. Examples of immune responses are the production of toxic compounds and the activation of other immune cells.

So how are the intruders perceived in the first place? Invading particles are recognized by the so-called B cells and T cells. These immune cells have receptors in their cell membrane, the membrane that separates the inside of the cell from the surroundings. On the outside of the cell, these receptors have structures that recognize (parts of) non-self particles. You can visualize this as a lock and key, with the receptor structure being the lock and (part of) a certain invading particle the key. When the particle fits on a receptor, the receptor is activated, leading to structural changes of the inner part of the receptor. These structural changes start a signaling process that ultimately results in an immune response.

While this system works against many disease-inducing agents, we all know that our immune system is not always successful. One example in which the immune system is not always successful in clearing away the disease-inducer is cancer. Because of this, humans have developed several therapies to treat this disease. However, these do not always work. In their recently published paper Roybal and his coworkers describe their work on harnessing properties of the T cell to develop a new treatment method.

The treatment method developed by Roybal and his colleagues is based on making synthetic T cell receptors. The part of these receptors on the outside of the cell can be designed to recognize any molecule. Upon activation, the receptor gets cut in half at the membrane, releasing the part inside the cell. This part can be designed to activate almost any gene – that is, a part of the genetic code coding for a particular protein. In theory, an engineered T cell with this receptor will result in a very specific, human-defined response upon recognition of the targeted disease-inducing particle.

The researchers tested the method by developing a receptor that recognizes a certain part of cancer cells. T cells with this receptor in their membrane were then cocultured with cancer cells. To easily test whether the synthetic receptor can drive activation of a specific gene, the inner part of the receptor was first engineered to drive activation of a gene encoding a fluorescent protein. Thus, if the receptor functioned as hoped, cells encountering cancer cells would become fluorescent. Excitingly, when exposed to the cancer particles, and only then, these T cells indeed became fluorescent.

Of course making a T cell fluorescent does not directly help curing cancer. Therefore, the researchers next wanted to see whether recognition of the cancerous cells could lead to effective immune responses. Again, the receptor performed as hoped: upon activation it could drive the secretion of proteins that shape the immune response, so-called cytokines, and the differentiation of immune cells into cells with anti-tumor fates. Moreover, cells could be engineered to induce the secretion of several therapeutics, resulting in cancer cell death. This is all the more exciting because some of these therapeutics are non-functional or toxic in the human body when delivered by injection. When delivered by the synthetic T cells, they are only delivered close to the tumor, preventing the side-effects.

While promising, the experiments described so far were all conducted on cell cultures. The immune responses of the engineered T cells might thus not be beneficial or even activated at all in organisms. Therefore, as a final experiment described in their paper, the researchers tested whether the engineered T cells also produce therapeutic agents when injected into the blood of a mouse with cancer. Not many T cells ended up in the tumor, but those that got there, and only those, did secrete the intended therapeutic agent. In a second experiment with a T cell receptor driving secretion of a different therapeutic agent, injection of the T cells resulted in clearance of the tumor.

While more research is needed before engineered T cells can be used in humans, the results published are very promising for two reasons. First of all, engineered T cells deliver their therapeutic agents locally at the site of disease. This prevents possible toxic effects of the agent when present throughout the body and ensures high doses at the right place. Second, at least in theory the receptors can be engineered to recognize any particle and lead to the activation of any gene. Since the engineered cells travel throughout the body, this means that injection with synthetic T cells has potential to treat many diseases.

Roybal, K.T. et al (2016) Engineering T Cells with Customized Therapeutic
Response Programs Using Synthetic Notch Receptors. Cell 167, 419-423.
DOI: http://dx.doi.org/10.1016/j.cell.2016.09.011

Disclaimer: blog posts in the category ‘journal club’ are not intended to cover the whole paper discussed. Instead, I discuss the parts that I think are most interesting for a general public. I try my utmost to prevent any mistakes in these blogs, I apologize in advance for any mistakes that I make anyway.

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