How to spur lymphocytes?
Substances capable of "awakening" lymphocytes to fight cancer have been found
Polina Gershberg, Naked Science
T-lymphocytes, also known as T-cells, are responsible for recognizing and destroying threats to the body. They attack both an external enemy, such as bacteria and viruses, and an internal one, such as tumor cells. With the development of cancer, the proliferation and functioning of T-lymphocytes are disrupted, they become dysfunctional – or "depleted".
One of the ways to treat cancer – immunotherapy, which is actively developing now, is based on the abilities of T cells. They must recognize the enemy and help destroy him. Accordingly, the main task is to revive these lymphocytes by selecting the most effective combination of drugs for this. The method proposed by scientists allows you to sort through possible compounds very quickly: the authors have already discovered 19 working compounds, having processed 12 thousand possible variants.
"This new screening method should be particularly useful because we can use it not only to identify compounds that restore the necessary function of depleted T cells, but also for rapid analysis to determine how these compounds affect them," explains senior author Dr. Michael Oldstone.
The approach described by scientists from the Scripps Research Institute in a study published in Cell Reports (Marro et al., Discovery of Small Molecules for the Reversal of T Cell Exhaustion) may also help restore T cell responses to persistent infections caused by viruses or other pathogens. It will accelerate the development of new methods of immunotherapy for cancer and infectious diseases. Some of these methods can be combined with existing immunotherapeutic drugs for enhanced joint effect.
The new method of searching for substances that awaken weakened T-lymphocytes is based on the work of a team of authors and their colleagues over the past decades. Initially, model animals were used to study how the immune system reacts to the lymphocytic choriomeningitis virus (LCMV). A unique variant of LCMV, known as "clone-13", depletes virus-specific T cells. He achieves a continuous course of infection by amplifying signals through T-cell receptors, such as PD-1 and IL-10. In the same way, by "turning off" T-lymphocytes, cancer cells provide themselves with a comfortable environment.
Immunotherapy blocks the transmission of signals from PD-1 or similar receptors, which allows T cells to "recover" and fight tumor foci again. Thanks to this, immunotherapy can be very effective, and where chemo- and radiotherapy methods fail. However, now this treatment does not work equally well for all types of oncological diseases, because scientists suggest that cancer can inhibit multiple ways of inhibiting T cells. This suggests that a combination of immunotherapy aimed at different molecular pathways may be more effective than the current type of therapy.
Pharmacologically active compounds with small molecules can work better than existing modern immunotherapeutic drugs for injecting antibodies, or supplement them. The authors of the article say that the new method will allow you to find the maximum number of drugs and combinations.
The screening system they offer uses T cells that have been depleted by clone-13 LCMV and tracks signs of renewed activity in them. This activity is registered (or not) in response to the application of the tested compound. The advantage of the new screening system is that it is specific and highly automated. Thus, thousands of compounds can be tested within a few days, and only later the selected "hits" are tested on model animals. The most successful ones are then tested in studies where their effectiveness is evaluated in the therapy of human patients.
Simplified screening scheme. Mice are infected with a virus, and then depleted lymphocytes are taken from them. The activity of immune cells is restored with the help of drugs, and then they are tested on model animals. A drawing from an article in Cell Reports.
Oldstone notes that the new approach may benefit not only in the field of cancer treatment. It is flexible enough to adapt to find compounds that have a different type of effect on T cells. For example, it will be possible to look for those that weaken the activity of T-lymphocytes: this will help to detect active substances for the treatment of autoimmune conditions.
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