Within the last decade, immunotherapy has emerged as a promising and viable treatment for many patients suffering from cancer. This type of therapy takes advantage of a patient’s own immune cells in order to specifically target and eradicate tumor cells. In order to understand how this class of therapy works, we need to first review the basics of cancer and then explore how a patient’s immune cells recognize and attack cancer cells.

Cancer: the basics

At its most basic level, cancer is a disease of mutated cells. Most normal (non-cancerous) cells that make up the human body have a lifespan, of sorts. They can only grow and divide a certain number of times before they become senescent or die. This exquisite control of cellular growth is what prevents the various parts of our bodies from growing continuously, and as such it is incredibly important.

Sometimes, though, cells acquire mutations, or changes, in their DNA that alter their expected growth pattern. These mutations can happen through environmental insults, such as UV light or cigarette smoke, or they can happen randomly during the inherently error-prone process of cellular division. Many times, these genetic changes are either harmless or detrimental to cellular health, in which case the mutated cell poses no problem to human health. Occasionally, however, a DNA change is actually advantageous for the cell. For example, the mutation may allow the cell to bypass normal growth control checkpoints, facilitating rounds of division that surpass the normal lifespan of that cell.  In this case, the mutated cell has essentially just won the genetic lottery, and evolutionally speaking, it is much more fit than its neighboring, non-mutated cells.

When a cell acquires one of these growth-promoting mutations, it can divide quickly and robustly, causing the cells to pile up on one another and form the masses that we know as tumors. Further, because of the aforementioned error-prone process of cell division, tumor growth forms a vicious positive feedback loop: the more times a mutated cell divides, the more likely it is to acquire additional mutations. These new mutations can make the cells even more aggressive, allowing them to do things like migrate into the vasculature and travel to different places in the body (a process known as metastasis).  

The fact that cancer cells are ever-evolving and ever-changing is the reason that cancer is so incredibly difficult to treat. It is hard to target a living, adapting entity with static drugs, because the cancer cells can mutate to acquire resistance. This fact has led many scientists to conclude that the best way to fight a living disease may be to employ the living army within the human body: the immune system.

How the immune system fights cancer

In the last few decades, the field of cancer immunotherapy has exploded into both the scientific world and the world of cancer treatment. This therapy can take many different forms, from vaccines to antibody-based treatments to the use of live immune cells targeted to the cancer. At their core, though, the various immunotherapeutic approaches have the same goal: to manipulate the ability of immune cells to specifically target and kill cancer cells.  

In order to accomplish this goal, the immune system must be able to recognize cancer cells as dangerous and thus warranting attack. This recognition, though, it complicated by the fact that cancer is a disease of human cells. In fact, the immune system has been vigorously polished and pruned, via processes like positive and negative selection, to prevent it from attacking one’s own cells. Normally, this is a good thing, as it prevents autoimmunity.

How, then, do immune cells “see” cancer as being different from normal, healthy cells? The answer to this question lies in the highly mutated nature of the cancer cell. As mentioned above, cancer is formed by mutated cells whose mutations beget more mutations, producing tumor masses of heavily mutated human cells. Some of these mutations lead to the production of mutant proteins, which can be displayed on the cell surface (either because the mutated protein is a cell surface protein, or through normal antigen presentation processes). When this occurs, the mutated proteins serve as a sort of danger signal, marking them as being foreign in a similar way to how bacterial or viral proteins alert the immune system to danger.

Once the immune system recognizes cancer as being foreign and dangerous, it can use its normal defense mechanisms to eradicate it. These strategies include attacking with the innate immune system, such as employing macrophage-based phagocytosis, and attacking with the adaptive immune system, via antibody production and direct cell-based lysis.

Cancer, in turn, employs many strategies to avoid immune recognition and immune-mediated killing, such as the expression of molecules like PD-L1 that dampen immune cell activation. This results in a real-time, evolutionary battle, with the immune system on one side and cancer cells on the other. Cancer immunotherapy, in its many forms, aims to tip the balance in favor of the immune cells, with the hope that that the immune system can once and for all put an end to the ever-growing cancer cell.

Featured image by Victor Segura Ibarra and Rita Serda, Ph.D. via NIH Image Gallery CC BY-NC 2.0