By Edgar Wex
Cancer is a very common disease affecting millions of people every year - however it is often untreatable due to its manipulation of the immune system to become essentially invisible to detection. But as with many biological interactions, there is an opportunity to access and change this pathway to reverse immunosuppression and treat the cancer. This treatment is called Immune Checkpoint Blockade (ICB) therapy.
To understand how it works, we must first understand how the immune system tries to fight cancer by itself. It begins with the expression of a neoantigen on a cancer cell’s surface. All cells routinely express various protein fragments on their surface to send a message of what they are doing and what they need. This antigen is recognised by an Antigen Presenting Cell, which in the presence of sufficient danger signals to indicate it is a threat, will pick up the antigen, process it, and express it on MHC II - a molecule that holds the antigen in a specific way to make it recognisable to other immune cells. The Antigen Presenting cell will express a chemokine receptor, which will get bound to chemokines and taken it into a lymph node through a lymphatic vessel. The lymph node is a sort of barracks for the immune system, where immune cells lie in wait until they are called upon to fight.
Inside the lymph node, the Antigen Presenting Cell will express the MHC molecule along with B7, which is a costimulatory molecule required for activation. As each lymphocyte in the lymph node is in a way ‘preprogrammed’ to fight one specific antigen, the Dendritic Cell will need to pour through thousands of these cells until it finds a match which will bind with the identified intruder. The T cell receptor on the T cell will bind to the MHC molecule, and the T cell's CD28 will bind to B7. This will signal activation and make the T cell replicate itself many times to produce an army, differentiate into various other subtypes of cells, and go to fight the cancer. After enough copies have been produced, the T cell expresses CTLA4, which is co-inhibitory, meaning when it binds to B7 it will shut off the activation. This is crucial for normal immune function as without it there would be too many activated cells, some of which may attack healthy cells.
However, this key step is also where cancer can come in to exploit the immune system. The crucial idea is that as CTLA-4 is inhibitory, its expression will block T cell activation. This will mean that less or even zero T cells are activated, and thus the cancer is safe from attack. Thus, CTLA-4 is expressed on cancer cells. CTLA-4 is usually only expressed on Treg (regulatory) cells, which carefully manage the immune system to prevent it from getting out of hand. When it is expressed on fighting T cells, it is expressed in very small quantities to avoid immune suppression - however when it is expressed, because it is much more reactive than CD28 (the immune activation molecule), it will immediately displace it and take priority to shut down the immune response. Thus, when CTLA4 is expressed on cancer cells, too much immune suppression occurs. CTLA4 can also remove B7 altogether from Antigen Presenting Cells through trans-endocytosis, thus reducing their availability and ability to later activate more lymphocytes.
However, this is only one molecule - there are more. These are called ‘immune checkpoints’, and act as regulators of the immune system to prevent the attack on healthy cells. The other major checkpoint is PD-L1 - the L indicating it is a ligand (meaning that it binds to) PD-1, which is expressed on T cells. Once fighting T cells have exited the lymph node and made their way to the tumour site, ready to fight, they should just attack the cancer straight away; and without the many methods of immune evasion that cancer uses, it would easily manage to destroy the cancer. However, the cancer cells can express PD-L1. When the PD-1 receptor on the T cell binds to something, it will essentially tell the T cell to go to sleep and stop fighting; the scientific term for these cells are ‘exhausted’ T cells.
So, both CTLA4 and PD-L1 are inhibitory molecules, which we need to survive and protect the body from an overactive immune system but are also very dangerous when hijacked by cancer cells. Luckily, there is a solution to this method of immune evasion; ICB therapy. All you would need to do is create something that will bind to CTLA4 or PD-L1 (or PD-1), which will stop the inhibitory interactions, and allow the immune system to fight cancer. This is done through monoclonal antibodies, as they can be mass produced and are simple enough that they will work in everyone’s body without causing an allergic reaction.
Monoclonal antibodies are made by combining myeloma cancer cells with antibody-producing splenic plasma cells, to form a hybridoma. The plasma cells produce antibodies but have a limited lifespan, while the myeloma cells are essentially immortal but don’t produce antibodies. This means most of the hybridomas will both produce antibodies and be immortal. The antibodies can then be harvested and purified and used straight away as a treatment. When injected into patients, they will block their respected immune checkpoint (CTLA4/PD-L1/PD-1) and release the cancer-induced brakes on the immune system. The antibody is named like ‘aCTLA4 mAb’, the ‘a’ meaning anti, and the ‘mAb’ meaning monoclonal antibody. There are also new emerging checkpoints which could be used in the future, like LAG-3 and TIM-3.
But why doesn’t this work for everyone? In theory it should, however there are some prerequisites required. For example, the tumour must already have a level of immune infiltration; meaning immune cells are present and are just not fighting - thus they can be reactivated through ICB. Alternatively, through immunohistochemical staining, the tumour could be found to be highly expressing PD-L1 or another checkpoint molecule, meaning it can be targeted. If these are not the case in tumours, and immune cells aren’t there in the first place, ICB will not be able to do anything as there is nothing to reactivate.
Citations
Image: https://flic.kr/p/2jzCvbj - Sam Levin, 24/8/20, no changes were made, License: Creative Commons Legal Code
What did you learn?
What does immune checkpoint blockade do?
Immune checkpoint blockade uses monoclonal antibodies to target immune checkpoints, such as CTLA-4 and PD-L1. These are inhibitory molecules which are sometimes expressed by cancer cells, which give them the ability to shut off the immune system and survive. The blocking of these molecules stops inhibition of the immune system and helps treat cancer.
Why isn’t immune checkpoint blockade used for every cancer patient?
Immune checkpoint blockade functions by releasing the brakes on the immune system. However, if there are no brakes in the first place, nothing would happen if you used ICB antibodies in a patient. Thus, a tumour needs to already have immune infiltration and inhibition to be treatable using ICB.