Cancer and the immune system: It’s complicated

In theory, it’s simple. Our immune system protects us and fights for our health and survival. In reality, scientists have spent decades trying to unravel and understand the complexities of the human immune system. These years of research have turned up some interesting quirks and some untold tales. So it is becoming clear that this isn’t as simple as we would like to think!

We all know when pathogens invade our bodies, the immune system kicks into action, like superheroes that swoop in to protect and defend. The human immune system has been elaborately developed over millions of years of evolution to patrol the body, constantly awaiting the signs of an invader. These signs are molecules, patterns or signatures on the surface of a pathogen called antigens that scream to immune cells “this is an intruder, man the walls, protect the castle”, and everything catapults into action. Cancer cells are no exception among those invaders. With cancer cells, the antigens tell the story of a cell gone wrong, perhaps a protein not quite right. This activates specialised cells of the immune system that help to remove cancerous cells and generate immunity.  This includes the assassins of the immune system, T-killer cells, which kill damaged, infected or cancerous cells; and dendritic cells that process antigens from cancer cells and display them like a wanted poster for the T-cells to act upon.

So, this raises a question. If the immune system can scout out these pesky intruders, why do we still get cancer? The answer to this lies in the fascinating yet sinister phenomenon of immunoediting. Cancer cells are sneaky, they have learned the secrets of our immune system and they use this information to adapt to their environment and avoid detection.

Immunoediting is a three step process that promotes tumour formation: elimination, equilibrium, escape. In patrolling the body, scouting out those transformed cancerous cells and killing them (elimination), the immune system is creating pressure on the tumour that causes it to generate immune-resistant cell variants (equilibrium). When equilibrium is reached, the immune system can still control tumours, but can no longer eradicate them. Only the most highly evolved and carefully adapted cancer cells are able to evade or defeat the immune system (escape). Cancer cells achieve this in a number of ways. They may reduce the number of antigens that help the immune system find cancer cells, thus affecting the action of dendritic cells. Alternatively, they might act on the killer T-cells. T-cells are so deadly that our immune system has several built-in checkpoints to ensure that their activity can be controlled. Cancer cells can exploit this, and increase their expression of ‘brake’ checkpoint proteins that cause the T-cells to pause, and allow the cancer to go undetected.

The good news? We’ve figured these processes out, and now we can play them at their own game. The pioneering concept of stimulating the human immune system to destroy cancer cells defines a new era of cancer treatment. Advances in these immunotherapies represent a shift in the way we manage and treat cancer. It’s such a hot topic that in 2018, James P. Allison and Tasuku Honjo were awarded the Nobel Prize for Physiology and Medicine for their work on immunotherapy.

So far, there are 5 main categories of immunotherapy, with some great success stories:

  1. CAR T-cell Therapy

Extract blood from a cancer patient, send it to the lab, they send it back, it fights the cancer… seems impossible, right? CAR T-cell therapy is a brilliant example of the dawning era of personalised medicine. By extracting the blood of a cancer patient, isolating the T-cells and genetically engineering them in the lab, we can re-programme cells of the immune system to improve the efficiency with which they can find and kill cancer cells in the blood. These T-cells are multiplied in the lab and are reinjected back into the very patient from which they originated – a truly remarkable ‘living therapy’.

  1. Checkpoint Inhibitors

There are several types of checkpoint inhibitors, all of which effectively release the “brakes” on killer T-cells. They target those over-expressed proteins on cancer cells that are tricking the T-cells into missing the cancer. This is perhaps one of the more advanced fields of immunotherapy, being applicable to patients with melanoma, Hodgkin’s lymphoma, non-small cell lung cancer and urothelial cancer, and currently in clinical trials for breast cancer.

  1. Monoclonal Antibodies

Monoclonal antibodies truly are at the heart of personalised medicine. These are exquisitely specific antibodies that can bind to proteins on the cancer cell surface like a lock and key, and act like a flare recruiting cells of the immune system to attack the cancer cell. Alternatively, these antibodies can bind to cells of the immune system, like those checkpoint proteins acting as brakes, to unleash the full potential of the immune system. There are 9 monoclonal antibodies currently recognised such as Trastuzumab which binds the Her2 protein characteristically expressed on certain breast cancer cells.

  1. Cancer Vaccines

Cancer vaccines represent an interesting approach to immunotherapy, acting to boost the natural cancer immunity cycle. Injection of cancer-specific antigens along with some adjuvants (like vitamins for the immune system) “awakens” immature dendritic cells and activates the immune system. This 2-fold strategy encourages the identification and destruction of cancer cells and generates an immunological memory of what the cancer cells look like, so the immune system can leap into action quickly when needed. There are ongoing clinical trials for cancer of the breast, lung, colon and prostate, among others.

  1. Cytokines

Cytokines are the true messengers of the immune system, they allows cells to communicate with one another and interact to initiate a response to an invader, they’re the things that make stuff happen! Cytokine is a broad term covering several large families of proteins that mediate the activity of the immune system and they can be enhanced and manipulated to boost immune response for therapeutic benefit. Examples include interleukin-2 and interferon alpha

It is, nonetheless, important not to sensationalise these revolutionary therapies. Of course they are inspiring, but they are not completely perfect and, as with any new drug, issues around safety, side-effects, cost and many other factors must be considered. It is early days, but this truly is awe-inspiring stuff happening right now and it is set to change the face of cancer medicine. We don’t know exactly what the future will bring, but we can be excited about it!

 

Blog written by Kate McSweeney