The Nobel Prize in Physiology or Medicine has just been announced. Professor James Allison and Professor Tasuku Honjo have won the Nobel Prize for their revolutionary contributions to an important understanding in immunology and its potential application in cancer therapy. The topic has led to my fond memories of taking immunology lectures in my undergraduate years. Here, I will share with you the Nobel Laureates' contribution to the understanding of 'negative immune regulation' and its inhibition to unleash the powers of immune cells.
The concept of the immune system is extremely complex because it entails a lot of molecular and biochemical events, so I will just describe the key processes here. The immune system defends us from various sort of microbes, because it has the ability to distinguish 'self' (the host’s body) from 'non-self' (the microbes). One of the most important players in the immune system is the T-lymphocytes (‘T-cells’). The T-cell is further categorized into cytotoxic (CD8) T cells and helper (CD4) T cells.
The CD4 T-cell is a like a midfielder in a soccer game, because upon its activation, it will lead to the downstream processes for the other components of the immune system, such as cytotoxic (CD8) T cells, to deal with and hence eliminate the enemy. The CD4 T cells achieve this end by engaging in the process of antigen presentation, where they 'present' a fragment of the broken-down microbe to an antigen-presenting cell (such as dendritic cells, macrophages and B lymphocytes). The resulting molecular interaction leads to an activated response, which serves as a signal for the other immune cells to take further action. Furthermore, a co-stimulation is often required to lead to a full and total immune response, and this is achieved by some activator proteins.
So, what's the deal with a nice guy helping us around to deal with the party-crashers? Well, if the immune system goes way too far off the map, the result can be catastrophic. Through genetic, environmental, or pathological factors, the immune system may over-react and in turn attack the host's healthy cells because it is misled to act in that way. The result is a variety of autoimmune diseases, and many of these can have drastic consequences for the host.
The immune system has been evolved throughout humanity to deal with this potential pitfall. Immunologists have discovered a number of inhibitory proteins, which serve as ‘brakes’ to balance out the action of the activator proteins. It is through this mechanism that a regulation is possible for the immune system, and this tight control is a theme in many biological systems.
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| (Top) Under normal circumstances, the CTLA-4 and PD-1 proteins will inhibit the T-cell response and serve as brakes to the immune system in 2 different mechanisms. CTLA-4 competes the active site with the activatory proteins, while PD-1 inhibits the T-cell response by binding to an alternative site on another (in some cases, cancerous) cells. PD-1, which stands for Programmed Cell Death 1 protein, presents a more complex scenario because while it can prevent autoimmune disease by suppressing the immune system from overacting in a normal body, it will cause problems in a cancerous case because the immune system is suppressed by its action. (Bottom) Anti-CTLA-4 and Anti-PD-1 are used to block the action of the two brake proteins, releasing the immune system to take care of the cancerous cells. [Source: https://www.nobelprize.org/prizes/medicine/2018/press-release/ ] |
What do these discoveries have anything to do with cancer therapy, then? Over the past century, researches have tried to find different approaches for cancer therapy. What is rather ironic is that our guardian angel - namely our immune system - has not been successful in the contribution to cancer therapy. Some researchers have even gone as far as adopting Edward Jenner's logic of vaccination to provoke a 'cancerous immune response', yet their efforts prove futile.
Professors Allison and Honjo have respectively developed similar insights to harness the negative immune regulation. Because if there is a way to stop the action of the brake (CTLA-4 and PD-1), then the immune system can be unleashed in full force to do the job, especially in the face of serious disease such as cancer. The solution is to use a specific antibody that can bind to and inactivate the ‘brake’ proteins. Thus, antibodies, known as anti-CLTA-4 and anti-PD-1, have been developed, and both research groups have successfully demonstrated that the antibodies can inhibit the ‘brake’ proteins. The immune system is released from the grip of the ‘brake’ proteins and thus can turn NBK on the cancer cells. (In fact, there is a type of immune cells called Natural Killer cells!). The two teams have successfully proved their ideas in some animal models, and the discovery has led to the development of ‘immune checkpoint therapy’.
The beauty of the discovery lies in the fact that, through the understanding of an important regulatory mechanism, a novel approach to cancer therapy can be devised and that will benefit cancer patients in the long term. The experiments the researchers have carried out to lead to this discovery also serve as a testament to the caliber of modern molecular biology, an intensely fascinating field on its own right.
by Ed Law
1/10/2018
