2018 Nobel Prize in Physiology or Medicine: The discovery of cancer therapy by inhibition of negative immune regulation
Having worked in the field of cancer immunology I am super excited to get to explain to you the immunology behind this year’s Nobel prize in Physiology and Medicine. There is a bit of basic (how stuff works) immunology but, hang in there, it’s worth it to find out about the discovery and development of immunity boosting, cancer killing therapy.
To help you understand this Nobel prize winning work, I want to introduce you to a couple of my favourites (they are not children, I’m allowed to have favourites). The first, in no particular favouritism, are natural killer cells (NK cells), and you guessed it, they are good at killing. The second are CD8+ T cells (cytotoxic T cells or cytotoxic T lymphocytes), despite the less impressive name, they are also expert killer cells so let’s call them killer T cells (FYI the T stands for thymus because that’s where they are made). These killer cell types are collectively referred to cytotoxic lymphocytes, but let’s just call them killer immune cells.
You might wonder why the body had two murderous immune cell types. Well, the bugs (microorganisms) that infect humans have evolved alongside us and as such, are good at hiding from our immune system. For example, viruses cannot survive for very long out on their own and cannot divide without taking over the cells of another organism (human cells, animal cells, plant cells, even bacterial cells), this means that they have to live inside cells. For bacteria, they typically live outside of cells, but some have worked out ways to hide themselves from the immune system by live inside our cells (intracellular bacteria). Luckily our body is (usually) too clever for these bugs.
Constantly while they are doing their cell thing, normal cells stick out little flags with bits of all of the proteins they are producing so that they can be scanned my immune cells. When the right killer T cell comes along and finds a cell showing a non-human protein, the killer T cell gets activated and kills the infected cell. This prevents the infection from spreading to other cells. Some viruses and bacteria have figured this out, so they turn off the flag system so that the cell stops showing off its proteins. This is where the natural killer cells come in to play. When they see a cell that doesn’t have any flags out, they know that something is suspicious, and they kill the cell.
Having natural killer and killer T cells whizzing about killing bacteria and virus infected cells is a great thing. But sometimes the immune system can get over excited causing damage to tissues and even targeting and killing cells that are not infected (as happens in autoimmune diseases). Luckily your body has several systems to prevent this from happening. One is for killer immune cells to have ‘brake’ signals that other cells (immune and non-immune cells) can press to stop and sometimes disable the killer immune cells. These are called immune checkpoints.
The last key point that you need to know is that cancer cells are your body’s cells gone bad. In theory, your immune system can find these cancer cells and get rid of them because they look different to other cells: they make proteins that they shouldn’t (making them killer T cell targets) and they stop sticking out their flags (making them natural killer cell targets). But obviously this doesn’t always work which means that they can also hide from or turn off the immune system.
Now for the work that was awarded the Nobel prize.
Professor James P. Allison and friends discovered that a protein found on the surface of killer T cells called CTLA-4 (long version of the name is cytotoxic T-lymphocyte–associated antigen 4), is one of the stop signals (checkpoint inhibitors) for killer T cells. Importantly, he was the first to show that blocking one of these stop signals releases the killer T cells so that they can kill cancer cells and activate other immune cells. Of course, he blocked CTLA-4 because that’s the stop signal that he worked on.
At the same time Professor Tasuku Honjo and friends discovered a protein called programed death 1 (PD-1). This protein is like a self-destruct button for killer T cells. They also found a protein that activates PD-1, called PD-L1 (the L stands for ligand which really just means binding partner), which is found on normal cells and cancer cells. Blocking PD-1 or PD-L1 stops cancer cells from hitting the self-destruct switch on activated killer T cells meaning they can continue eradicating the cancer cells.
Both of these discoveries (which come from decades of research) prove that blocking the stop signals (checkpoint inhibition) on killer T cells boosts your immune system enabling it to cure cancer. And because killer T cells are one of the immune cell types that has memory (yes some of immune cell types have memory, this is why vaccines can protect you for years), it is thought that boosting your killer T cells will also help to prevent the sneaky cancer from coming back. For the scientific field, this work is especially exciting because it is a prime example of how investment in basic science research (i.e. research to understand how things work) can lead to medical breakthroughs and it brought back to life interest in the long-neglected concept of using the body’s immune system to fight cancer (immunotherapy).
