Immunotherapy: awakening the immune system to fight cancer

Biomedical Sciences, cancer, Immunology

By Ross Keller, PhD candidate in Biomedical Science.

What is the immune system?

The human body is continuously under assault from a wide array of things that would do it harm. Many of these come in the form of pathogens—or microbes that infect the body and are not part of the body’s flora. These microbes range from common cold viruses to pneumococcal bacteria to deadly viruses like Ebola.

macs_killing_cancer_cell

Immune cells attack a tumor cell (spiky cell in center). (Wikipedia)

However, the body can also come under attack from itself in a number of ways. One manner this occurs is when normal cells transform and begin dividing uncontrollably. Over time the rogue cells begin invading organs and destroying their normal function—this is known as cancer.

But, the human body has been evolving for millions of years, and over that time it has developed an extensive and complex defense system to ward off outside invaders like pneumonia as well as home-grown usurpers like cancer. It is termed the immune system.

The immune system is a complex network of non-specialized and specialized cells that each have a role in keeping the body safe. It can be divided into two broad categories: innate and adaptive. The innate immune system is the body’s way of attacking pathogens in a generic way, meaning many types of invaders will be treated equally—it acts fast. On the other hand, the adaptive immune system is composed of specialized cells that remember the specific type of invader and mount a specific attack when the invader is encountered a second time—it acts slowly the first time and quickly the second.

What is the immune system’s role in cancer?

metastatic_melanoma_cells_nci-vol-9872-300

Melanoma cells dividing rapidly. (Wikipedia)

The immune system is generally considered to have three main roles in preventing cancer— two indirect, and one direct. The first is to eliminate viruses, several of which have been linked to an increased risk for cancer. The second is to clear pathogens quickly to eliminate any inflammation that could produce an environment beneficial to a tumor. The third involves a direct way that the immune system protects from cancer, and that is called “immune surveillance.” (1).

Normal cells have receptors on their surface that the immune system recognizes—it’s a way that the cell can tell the immune system that it is “self” and supposed to be there. But, something happens when a cell’s genetic material begins to change, leading to the beginnings of cancer. The change in genetic material puts the cell under stress, and as a result, it begins to express receptors that are abnormal. The immune system can see these too, and in turn, it eliminates the precancerous cells. It’s the body’s way of recognizing a cancer cell before it begins to grow—or the body’s “surveillance” of the potential cancer.

How does cancer outsmart the immune system?

But, cancer does happen, which means cancer can sometimes outsmart and evade the immune system. The process is Darwinian in nature, meaning the cancer cells evolve and certain genetic changes are selected that grow out. One such adaptation that can cause a cancer to grow out is a genetic change that makes the precancerous cell “invisible” to the immune system. A way this happens is some cancer cells start expressing a receptor called PD-L1.

t-cell-with-receptor

Receptors sit on the cell surface. They are used by the immune system to identify cells of the body and potential intruders. (Pixabay)

PD-L1 is a protein that sits on the cell’s surface. The way PD-L1 works is it recognizes a protein on the surface of an immune cell and tells the immune cell to “halt.” This stops the immune cell from killing the cell that expresses PD-L1.

In normal cells, it is a way the body stops the immune system from attacking itself. During events such as pregnancy, the body needs a fail-safe to keep the immune system from destroying newly formed tissue. It is also a check on auto-immunity. The body upregulates these proteins in select tissues when the immune system is overactive, such as with Lupus, or hepatitis (2).

But, cancers find a way to co-opt this mechanism of avoidance. During evolution, the cancer cells that express the PD-L1 protein are favored, and they continue to divide, meaning the whole tumor has now found a way to outsmart the immune system. The tumor tells the immune cells that are supposed to kill it to “halt,” and the immune cells listen, allowing the cancer to grow.

Can it be reversed?

There is a new wave of drugs being developed to harness the power of the immune system to treat cancer. One way is using drugs to block the interaction of the PD-L1 protein with the immune cells. The effect of this is stopping the cancer from being able to tell the immune system to “halt,” which means the immune system is now free to attack one the tumor once again.

presidents_obama_clinton_and_carter

President Jimmy Carter (right) pictured with Presidents Obama and Clinton. President Carter underwent treatment with Keytruda at age 90. (Wikimedia Commons)

So far, the drugs have shown promise. One drug, Keytruda (pembrolizumab), targets the PD-L1-immune cell interaction (3). It received recognition in the news because it was the treatment President Jimmy Carter received to treat his advanced melanoma, which had spread to the brain. Using more conventional therapies, the outlook for melanoma that had spread to the brain was bleak, but many patients, including the former President have responded well and remain in remission today.

Immunotherapy is a new frontier in the fight against cancer. New methods of immunotherapy are being developed all the time, including engineering “super immune cells” that fight specific cancers for specific patients. More on those in a later post.

 

  1. Swann, Jeremy B., and Mark J. Smyth. “Immune surveillance of tumors.”The Journal of clinical investigation5 (2007): 1137-1146.
  1. Chemnitz, Jens M., et al. “SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation.”The Journal of Immunology 2 (2004): 945-954.
  1. Burns, Michael C., Aidan O’donnell, and Igor Puzanov. “Pembrolizumab for the treatment of advanced melanoma.”Expert Opinion on Orphan Drugs just-accepted (2016).

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