September: Blood Cancers

Using protein therapies as multitools for cancer treatment

Melissa Evans, BSc.
Contact: mevans72@uwo.ca
Sept 2021

Before cancer treatments can be tested in patients, extensive research is done to understand the basic biology behind what treatments do at a molecular level. One challenge facing cancer researchers is that no two cancers are the same; however, some may have similar markers or proteins on the cancer cell exteriors that allow doctors and researchers to tell them apart. These exterior proteins are also possible targets for therapies, so understanding the different markers and their role(s) in cancer progression is important.

Often, cancer treatments are designed to kill one subtype of cancer. Within the most common type of blood cancer, lymphoma, there is T cell lymphoma, a type of cancer where T cells begin to divide uncontrollably starting in the lymph nodes. Blood cancers such as lymphoma circulate throughout a patient’s system and provide easier access for studies and the delivery of cancer therapies which is why they are often researched when translating from basic biology to testing therapies. This means treatments for blood cancer are usually developed faster and approved more quickly for clinical trials, and the same/similar treatments are later tested and applied to other types of cancers.

The cancerous cells in lymphoma (and in most other blood cancers) are mutated immune cells. The immune system is composed of a complex network that includes many types of white blood cells (immune cells), which work together to defend the body from infections. This system can keep a record of every germ it has ever come across and defeated, so that the next time the same germ tries to attack the body, it can be destroyed quickly. This is the same principle of immune memory that vaccines rely on. This memory system is known as adaptive immunity. The adaptive immune system, accounting for a portion of the immune system, is made up of specialized white blood cells – largely T cells and B cells. There are different types of T cells, and killer T cells are responsible for destroying infected or diseased cells. The white blood cells are important for memory, fighting infection, and even fighting cancer, but can mutate to become cancerous themselves, as is the case in T cell lymphomas.

All over the surface of cells are proteins that interact and send signals between cells, telling immune cells when to act and react. As cells move around the body, particularly in the blood, they bump into each other and their proteins interact. When the cells interact and communicate, it is important for immune cells to check if cells are infected or cancerous so that healthy cells are not killed. This is why T cells need to be activated through special cell signallers called T cell receptors (Fig. 1-A). Sometimes proteins tell the T cells receptor to de-activate the T cells (Fig. 1-B). One of these proteins is CD5. CD5 is found on T cells and at normal levels, regulates the T cell’s activation levels (Fig. 1-B). The problem is that in cancerous cells such as some T cell lymphomas, CD5 is too abundant. This essentially leads to CD5 acting as a shield, so when healthy immune cells such as killer T cells bump into these cancerous CD5 cells, it tells the T cells not to activate, and the cancer cells go unnoticed.

Figure 1. (A) Normally, T cell receptors control activation of all T cell types. (B) CD5 regulates the T cell activation and prevents accidental T cell activation. (C) When CD5 is blocked, it allows the T cells to be activated through the T cell receptor.

Researchers in the Departments of Microbiology & Immunology and Oncology at Western University and the London Regional Cancer Program, in collaboration with the Anticancer Drugs Research Laboratory at Al-Quds University, the Institute of Immunotherapy at Nanchang University, and Jiangxi Academy of Medical Sciences, conducted studies on the efficacy of using a CD5 blocker to improve killer T cell activation. A successful CD5 blocker could be useful in cancer treatments since it would keep T cells activated and in turn, increase cancer cell killing and reduce tumour growth (1). This study was done by testing the effects of blocking this CD5 protein to prevent the deactivation of killer T cells, using a protein that binds to and blocks CD5 (Fig. 1-B). When CD5 is bound by a blocker protein, it leads to less CD5 on the cell surfaces and increases the T cell activation (Fig. 1-C).

Figure 2: ex vivo experiment outline to isolate killer T cells which are tested for the effect of CD5 blocking.

The group performed several experiments on the efficacy of a CD5 blocker.  They injected cancer cells into mice to form tumours. After 3 weeks, T cells were then collected from the spleen of these mice, as well as from healthy mice without cancer for comparison. In an ex vivo experiment, the effect of the CD5 blocker was determined by measuring how well these T cells could kill cancer cells (Figure 2).

The researched showed that CD5 blocking molecules can help to overcome the effect cancer cells can have on decreasing killer T cell activation and improve the ability of killer T cells to kill tumours. One of the limits of this work is that CD5 is present on many cells, so this CD5 blockade system could lead to a general over-activation of T cells, and a poorly controlled immune response. Whether or not the benefits of increased cancer cell killing outweigh the broader effects of blocking CD5 is an important question that remains unanswered. Overall, this work has shown that blocking CD5 enhances killer T cell function. In the future, CD5 blocker could be tested as a potential approach to increasing killer T cell activation in solid tumours (i.e., breast, prostate) or as a supplement to bolster existing cancer treatments.

References

Alotaibi, F.; Rytelewski, M.; Figueredo, R.; Zareardalan, R.; Zhang, M.; Ferguson, P. J.; Maleki Vareki, S.; Najajreh, Y.; El-Hajjar, M.; Zheng, X.; Min, W. P.; Koropatnick, J., CD5 blockade enhances ex vivo CD8. Eur J Immunol 2020, 50 (5), 695-704. Original Article: https://onlinelibrary.wiley.com/doi/10.1002/eji.201948309

*Figures created with BioRender.com