How to fight cancer with the immune system? Immune checkpoints are the key

The immune cells in our body are the most natural protective umbrella when tumors appear. Before radiotherapy and chemotherapy, we could only rely on the immune system to identify and eliminate tumors. Unfortunately, most of the time, the immune system cannot resist the cunning tumor cells and ends in failure.

The now booming tumor immunotherapy is a return to the original, trying to reawaken immune cells through drugs or gene editing technology, helping them to accurately identify and destroy tumor cells without harming their own healthy cells. One of the key principles of this type of drug development is the immune checkpoints that are unique to immune cells . The drugs we often hear about, such as pembrolizumab, nivolumab, relizumab, kedeluzumab, and carrelizumab, are all designed to target immune checkpoints. Almost every year, new monoclonal or multi-antibodies targeting immune checkpoints are launched on the market, and there are as many as 126 such drugs undergoing clinical trials.

Figure 1. Anti-tumor drugs targeting immune checkpoints that have been marketed (Image from MedSci)

Since the incidence of tumors is so high and this type of new anti-tumor drug is becoming more and more popular, it is necessary for each of us to understand what immune checkpoints are, what these various monoclonal antibodies mean, and how they are related to immune checkpoints, so that we will not be completely ignorant when we need to face tumors.

1. Immune checkpoints: protection against indiscriminate killing of innocent people by immune cells

Immune cells are the most critical barrier against foreign bacteria and viruses, but once they fail to distinguish between friend and foe or become obsessed, the consequences are unbearable, such as triggering allergies, autoimmune diseases, cytokine storms, etc. Our immune system has evolved many ways to ensure that immune cells do not attack our own cells and shut down immediately after clearing pathogens, and setting up immune checkpoints is one of the ways.

Immune checkpoint refers to a phenomenon in which immune cells are "killed" or inhibited when they are overexcited. There is a special class of immune checkpoint proteins on the surface of immune cells, including the well-known PD1, CTLA4, etc., which represent the degree of excitement of immune cells and are also the objects of inspection by other cells. If the expression level is too high, the immune cell must be controlled.

It sounds quite magical, but how can it be controlled? How do cells communicate with each other? In fact, it is very simple: the immune checkpoint proteins carried by immune cells are often proteins that induce their own apoptosis, that is, the immune checkpoint proteins transmit suicide signals. Many of our own cells have target proteins that are paired with immune checkpoint proteins. Once the two are paired, the suicide signal is transmitted into the immune cells, causing the immune cells to die. The more excited the immune cells are, the more immune checkpoint proteins they carry, and the easier it is to be exposed and "killed". This is the principle of immune checkpoints to prevent immune cells from going astray.

2. Tumor cells can also initiate apoptosis of immune cells through immune checkpoints

The starting point of immune checkpoints is good, but unfortunately they are exploited by cunning tumor cells. Tumor cells also express many immune checkpoint target proteins on their surfaces. The excited immune cells were originally coming to eliminate tumor cells, but when the surface proteins of the two came into contact, the immune checkpoint proteins of the immune cells were activated, releasing suicide signals, and the immune cells died in vain, while the tumor cells were at large.

Because of this, monoclonal antibodies that protect immune checkpoint proteins came into being. The full name of monoclonal antibody is monoclonal antibody, which is a very pure antibody that specifically recognizes immune checkpoint proteins. After recognizing them, it binds to the immune checkpoint proteins, just like putting a helmet on it. The protected immune checkpoint proteins cannot be bound by tumor cells, so immune cells can naturally function normally and clean up these strange-looking tumor cells! Because the existence of these monoclonal antibodies terminates the inspection of immune cells by other cells, this type of monoclonal antibody is collectively called immune checkpoint inhibitors.

3. The difficulty in developing immune checkpoint inhibitors lies in improving efficacy and stability

Although it sounds like immune checkpoint inhibitors unleash the power of immune cells, only 10-30% of patients in clinical practice have long-term and effective cancer control after using this type of drug. Why do so many patients not respond to this therapy? Why do some patients develop drug resistance after a period of treatment? The main reason is that the efficacy of immune checkpoint inhibitors is affected by many factors, such as the tumor microenvironment, tumor antigen structure, immune cell number and function, whether intracellular signal transduction is normal, etc., and these factors often change, making it more difficult for immune checkpoint inhibitors to be effective in the long term.

The most typical example is that when an immune checkpoint protein on the surface of lymphocytes is protected by a monoclonal antibody, it will stimulate the expression of other immune checkpoint proteins, deliberately increase the chance of being recognized by other cells, and reduce its own activity. No one knows why lymphocytes do this, but it undoubtedly greatly weakens the effect of immune checkpoint inhibitors.

It is for the above reasons that scientists have begun to use two immune checkpoint inhibitors in combination, or to combine immune checkpoint inhibitors with other treatments, which can increase the effectiveness and stability of treatment to a certain extent.

Some friends may ask, since immune checkpoint inhibitors block the monitoring and control of immune cells, will they cause excessive immune response? Yes, the side effects of immune checkpoint inhibitors include adverse skin reactions, diarrhea, enteritis, pneumonia, joint pain, etc., which are all related to excessive activation of lymphocytes. Therefore, the dosage and time of medication are very critical.

The battle between tumor cells and immune cells never stops, just like the battle between masters in martial arts novels. Each time the two sides show each other some new moves, researchers and doctors try to help immune cells gain the upper hand by analyzing the moves of the two. Immune checkpoints are a constant source of inspiration for researchers to design anti-cancer drugs. I hope that the cure rate of immune checkpoint inhibitors can be higher and higher, so that more people will no longer suffer from cancer.

References

Liu J, Chen Z, Li Y, Zhao W, Wu J, Zhang Z. PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy. Front Pharmacol. 2021 Sep 1;12:731798. doi: 10.3389/fphar.2021.731798. PMID: 34539412; PMCID: PMC8440961.

Guo H, Bai R, Cui J. Zhongguo Fei Ai Za Zhi . 2020;23(2):101-110. doi:10.3779/j.issn.1009-3419.2020.02.05

This article is a work supported by Science Popularization China Starry Sky Project

Author: Zhao Bei

Reviewer: Wang Zhen, deputy chief physician of thoracic surgery, Cancer Hospital, Chinese Academy of Medical Sciences

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

Source: Starry Sky Project