Researchers at UCLA have managed to guide pluripotent stem cells into becoming adult T cells, the cells that patrol the body to kill cancer and other diseases and that are trained in our thymi.

The study, published in Cell Stem Cell, was led by senior author Gay Crooks, M.D., a professor of pathology and laboratory medicine and of pediatrics. Dr. Crooks is the co-director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

An army of T cells to fight cancer

T cells are normally produced by the bone marrow and trained by the thymus, a small organ located behind the breastbone, which sends them out into the body to patrol and destroy cancer and invading pathogens. The thymus starts to shrink quite early in life, and it trains ever-declining numbers of T cells as we grow older; this shrinking is known as involution, and the decline of the immune system is why we become vulnerable to diseases as we get older.

As described in the new study, Dr. Crooks and her team at UCLA have used artificial thymic organoids, small organlike structures that mimic the thymus, to produce and train human T cells [1]. The new approach uses these organoids to create mature T cells by using pluripotent stem cells. The organoids can produce a self-renewing supply of T cells, much like the thymus in your own body does while you are younger.







Pluripotent stem cells are cells that have the potential to change into any cell in the body, given the right signals to do so, and we have been able to create these on demand for well over a decade by using cellular reprogramming [2].

Having the ability to produce an unlimited army of T cells has implications for fighting cancer, particularly through immunotherapy, and it could also find utility in fighting infections, including HIV, CMV, and autoimmune diseases.

T cell therapies, such as CAR T cell therapy, have shown a great deal of potential for treating cancer; however, this currently relies on taking T cells from a patient, modifying them, and adding a new receptor to help them detect cancer cells and destroy them.

Unfortunately, the performance of these modified T cells is not always great, and the results can be hit and miss. Another problem with therapies like CAR T is the cost, as each therapy must be customized to each individual patient; this drives up the costs massively. Patients with cancer may also not have enough T cells left to take samples of.

All of these factors seriously limit the effectiveness of immunotherapy approaches using T cells. This new technique could potentially change all that.







Building on a previous study

The researchers have been working on this technique for a number of years and had previously demonstrated that they could create mature T cells in the artificial thymic organoids using adult blood stem cells. At the time, they hypothesized that they could achieve the same results by using pluripotent stem cells, and this new study is a vindication of that.

The researchers have shown that the artificial thymic organoids can use both embryonic stem cells and induced pluripotent stem cells, the two types of pluripotent stem cells used in research. Induced pluripotent stem cells are the easiest stem cells to obtain, as they can be easily and reliably created by reprogrammed adult skin cells or blood cells.

The researchers were also able to genetically modify the pluripotent stem cells so that they expressed a cancer-targeting T cell receptor, which, when combined with the artificial thymic organoids, was capable of creating T cells able to detect and destroy specific tumors in mice. The plan would be to create genetically modified pluripotent stem cells lines that can then create tumor-specific T cells.

Many cancer cells evade the T cells by tricking them into ignoring them, thus hiding in plain sight. These tumor-specific stem cell lines could be produced in unlimited amounts to provide an endless army of T cells that seek and destroy cancer no matter where it tries to hide.







One last hurdle to overcome

While this is great news for immunotherapy, there is one remaining hurdle to overcome. The T cells created using this approach have marker molecules on their surfaces that are not patient-matched and could provoke the patient’s body to reject the new cells.

The researchers’ next step will be to create human T cells that have the receptors needed to combat cancer but lack the molecules specific to immune rejection so that the patient’s body will accept them and not see them as invaders. These cell lines could then be produced in unlimited amounts and used in immunotherapy.

Such a technique could produce unlimited T cells without the need to harvest them from any source, nor would it require modifying them to avoid immune rejection. This would be a huge leap for immunotherapy and would make such treatment both cost-effective and accessible. It is not hard to envision ‘off-the-shelf’ T cell therapies being used for cancer and many other diseases in the near future.

Conclusion







Having an unlimited supply of universal T cells capable of taking the fight to cancer would be a real game changer, and these researchers seem to be closing in on that ultimate goal. Using modified immune cells to kill cancer is the ultimate solution in the war on cancer, and we are enthusiastic about the advantages of such an approach over approaches such as chemotherapy and radiotherapy, which are harsh and do considerable damage to the patient.

From the point of view of aging research, it is also not hard to imagine that such on-demand T cell production might also be used to bolster aging immune systems; perhaps, in time, we might receive thymic organoid transplants to replace our own thymi, which waste away with age.

We live in a very exciting age of medicine, and the approaches we have close at hand represent huge steps forward that could change how we treat disease forever.







Literature

[1] Montel-Hagen, A., Seet, C., Li, S., Chick, B., Zhu, Y., Lopez, S., … & Casero, D. (2018). Directed Differentiation of Conventional T Cells From Human Pluripotent Stem Cells in an Artificial Organoid System. Experimental Hematology, 64, S51.

[2] Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. cell, 126(4), 663-676.