Sculpted to a T: Synthetic T-cells for a more controlled immune response

Author: Holly Wobma, 10/18/16

I have a confession.  This is not a blog about stem cells.

It is, however, a blog about cells with infinite possibilities of fate. Because we are entering the world of synthetic biology, where crafty cellular engineering has enabled a new level of control over immune cell function.

This work comes out of Wendell Lim’s lab at UCSF and is featured in the latest issue of Cell.  .

As background, our body contains lymphocytes called T-cells, and each T-cell has surface receptors that recognize a very specific protein or “antigen.” To cover the diversity of antigens we might encounter, we have a broad spectrum of T-cells with different receptor specificities. During an infection or other sort of disease state, the T-cells that recognize a particular foreign antigen will be activated and will replicate to try to meet the challenge.

Now for those familiar with emerging cancer therapies, you may have heard of something called a “CAR T-cell”.  (Signals’ blogger Mark Curtis has written about them frequently in his Cell Therapy Deal Review.) This stands for chimeric-antigen receptor. The idea is to engineer T-cells to have receptors that recognize tumour antigens. The hope is that these CAR T-cells can be introduced as cell therapies to reduce tumour burden, and while extensive trials are still underway, many clinicians and scientists have high hopes of success.

Nevertheless, in Dr. Lim’s view, CAR T-cells have some limitations. Even though you can control which antigens they recognize, they can still be influenced by other environmental signals that may impede their ability to respond. For example, one of the reasons tumours can be so difficult to eradicate is that they express suppressive factors that shut down cells that would otherwise attack them (e.g. a CAR T-cell).

To help overcome tumour immune escape, numerous drugs classified as “checkpoint inhibitors” have recently been in development and function by blocking these immunosuppressive pathways (e.g. PD-L1, IDO inhibitors).

However, Dr. Lim takes a different approach. His idea is to not only control which antigens a T-cell will recognize (like CAR T-cells), but to also directly link antigen binding to a defined gene transcription program. Thus, as soon as a T-cell binds the antigen of interest, it will behave in a predictable manner that will be minimally influenced by other environmental cues.

His lab accomplishes this by taking advantage of the biology of the Notch receptor. This transmembrane protein has an extracellular recognition region, which is linked to a temporarily bound intracellular transcription factor via a regulatory domain. When the substrate binds to the receptor, the regulatory region cuts off the transcription factor, allowing it to promote gene transcription. Of course, in the scenario of Dr. Lim’s “synNotch T-cells”, the recognition region and the transcription factor can be user specified using molecular cloning. Thus, you can define the cellular response you want upon exposure to a specific antigen.

Figure 1: Synthetic Notch (SynNotch) T cells have antigen-specific receptors that upon recognition of the antigen of interest, mediates the release of an encoded transcription factor. This technique allows for controlled expression of 1) cytokines, 2) T cell differentiation genes, 3) cytotoxic genes, or 4) antibody production. (Roybal et al. (2016) Cell 167:1-14) Illustration by Carmen Wong, CCRM

Figure 1: Synthetic Notch (SynNotch) T cells have antigen-specific receptors that upon recognition of the antigen of interest, mediates the release of an encoded transcription factor. This technique allows for controlled expression of 1) cytokines, 2) T cell differentiation genes, 3) cytotoxic genes, or 4) antibody production. (Roybal et al. (2016) Cell 167:1-14) Credit: Carmen Wong, CCRM

To show the power of this technique, Dr. Lim’s lab creates T-cells that recognize tumour antigens and then elicit different responses based on the transcription factor that was encoded. In one scenario, they engineer T-cells to produce massive amounts of a specific cytokine (e.g. IL-2 or IL-12) upon antigen binding. In other scenarios, they show they can  control T-cell differentiation; create cytotoxic CD4+ T-cells; and, create antibody producing T-cells.

Of course, while synNotch T-cells are exciting for the field of oncology, they also hold potential for other applications such as autoimmune disease. One could opt to either eliminate auto-antibody producing B-cells, as has been attempted recently in a modified CAAR T-cell therapy, or even create antigen specific regulatory-like T-cells programmed to promote immune tolerance to a specific antigen (e.g. a self-antigen that is generating an autoimmune disease).

The possible synNotch T-cell concoctions and applications appear to be unlimited. While I’m not totally clear on how long these T-cells mount a response and how they will eventually be eliminated, they will likely behave outside our preconceived notions of an immune response. Indeed, if you even think about how odd it is to have an antibody producing T cell, it makes you realize how much we take for granted about cell functions that we actually have the ability to control.

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Holly Wobma

Holly Wobma

MD/PhD student at Columbia University
Holly is an MD-PhD student at Columbia University in New York. She recently (2011) completed a Bachelor of Health Sciences Honours Degree from the University of Calgary, where she pursued research related to nanotechnology and regenerative medicine. In addition to research, she enjoys participating in science outreach roles. Previously, she contributed to an award-winning Nanoscience animation produced by the Science Alberta Foundation (“Do You Know What Nano Means?”), and served on the board of directors for the Canadian Institute for Photonic Innovations Student Network. Holly's lab tweets @GVNlab.
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