Understanding the Immune System

Immunotherapy is a fundamentally different approach to treating melanoma and other cancers. It involves the use of the same natural defenses a body uses every day to fight infection. In some patients, the cancer is able to trick the body’s immune system so that cancer cells can “hide” in plain sight.

Immunotherapies help the immune system recognize cancer as a foreign invader and help build on the healing capabilities of the immune system with drugs and other techniques (see The Role of Monoclonal Antibodies). 

How the Immune System Works

The immune system is the body’s natural defense against infection and disease, including cancer, and protects the body from substances that can cause harm, such as bacteria and viruses (also called germs). The cells of the immune system continuously flow through the body, looking for germs that may be invading Imm_System_Fig_1.jpgthe body.

The immune system recognizes invaders by their antigens, which are proteins on the surface of the invading bacteria or on virus-infected cells (see Figure 1).

Every cell or substance has its own specific antigens, and a person’s cells carry “self-antigens” that are unique to that individual. Cells with self-antigens are typically not a threat. Invading germs, however, do not originate in the body and so do not carry self-antigens; instead, they carry what are called “nonself-antigens.”

The immune system is designed to identify cells with nonself-antigens as harmful and respond appropriately. Most immune cells release cytokines (messengers) to help them communicate with other immune cells and control the response to any threats.

Facing a Normal Invader

The immune system works constantly to keep the body free from infection. Understanding how the immune system responds in an ordinary situation will make it easier for your patients to see how it can be enhanced to face a more serious condition such as cancer. To help explain the immune system to your patients, use the following example:

When you skin your knee, for example, the immune system’s first barrier, the skin, is broken, and harmful substances can easily enter the body (see Figure 2).

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Words to Know

Antibody – A protein created by B cells in direct response to specific antigens. An antibody attaches itself to its respective antigen, marking it for other immune cells to “see” and destroy.

Antigen – A protein produced by a cell, virus or bacteria. In the case of cancer antigens, the protein or part of a protein on the surface of the cancer cell or substance that alerts the immune system. This causes the production of antibodies or creates T cells that can recognize and potentially destroy the cancer cell expressing that antigen.

Antigen-presenting cells (APCs) – Special cells that digest invading cells or soluble protein antigens and present them to the T cells and B cells so they know what to attack.

B cells – Immune cells that produce antibodies for specific antigens that will bind to the antigens and mark them for destruction by other immune cells.

Cytokines – Proteins released by immune cells to communicate with other immune cells; certain cytokines, such as interferon and interleukin, help regulate specific immune system functions.

Major histocompatibility complex (MHC) – A set of proteins on the surface of certain immune cells that influence the interaction of normal cells with immune cells. Antigen-presenting cells show digested antigens to T cells through the MHC on their surface, which allows the T cell to “see” the antigen and recognize it as foreign. The connection between the MHC and the receptor on the T cell is the first signal necessary to activate the T cell to respond to a tumor and destroy it.

Monoclonal antibodies (mAbs) – Antibodies made in a laboratory that are designed to target specific parts of cancer cells, which may include certain proteins or molecules on the surface of the cancer cells; they are meant to stimulate an immune response in the same way as naturally produced antibodies do.

T cells – Immune cells that recognize specific antigens during antigen presentation; T cells are the major players in the immune system’s fight against cancer. Their activation and activity are two of the main focuses in immunotherapy research.

Upregulate – Increase either the overall immune system response or the specific responses of certain immune cells.

As soon as the injury occurs, immune cells in the injured tissue begin to respond and also call other immune cells that have been Imm_System_Fig_3.jpgcirculating in your body to gather at the site and release cytokines to call other immune cells to help defend the body against invasion. The immune cells can recognize any bacteria or foreign substances as invaders. Immune cells, known as natural killer cells, begin to destroy the invaders with a general attack. Although this attack can kill some of the invaders, it may not be able to destroy all of them or prevent them from multiplying.

At the same time, other immune cells called dendritic cells start to engulf or “eat” the invaders and their nonself-antigens. This process causes the dendritic cells to mature into antigen-presenting cells (APCs). These APCs expose the invading cells to the primary immune cells of the immune system—the B and T cells—so that these cells can recognize the invading cells. B cells work rapidly to produce antibodies which help identify and stop the invading bacteria. Viruses, unlike bacteria, like to hide inside normal cells and may be more difficult for the immune system to recognize. T cells, however, are designed to find abnormal fragments of viruses inside normal cells. Before these T cells have been activated to fight viruses and other invaders, they’re known as “naïve” T cells.

APCs communicate with and activate the naïve T cells by connecting to them through protein molecules on their surfaces. A specific set of proteins on the APC, called the major histocompatibility complex (MHC), must connect to the receptor on each T cell. This first important connection is sometimes referred to as Signal 1. This connection allows the T cell to recognize antigens on invading cells as a threat (see Figure 3).

Before a T cell can be fully activated, however, additional molecules on the surfaces of both cells must also be connected to confirm that an attack against the invader is necessary. This second signal is known as the co-stimulatory signal, or Signal 2. If a T cell receives Signal 1 but not Signal 2, the T cell will die, and the attack is shut down before it even started.

When a T cell receives both Signal 1 and Signal 2, it is able to recognize the invading cells and destroy them. This fully activated, or effector T cell, then multiplies to expand the number of T cells that are equipped to defeat the threat (see Figure 3). Multiple generations of immune cells are created by the same immune response, and then some T cells transform into regulatory T cells, which work to slow and shut down the immune response once the threat is gone.

Other T cells may become memory T cells. They can stay alive for months or years, continuing to fight off the same invading cells again. Memory is the basis of immune protection against disease in general and explains why we don’t become infected with some diseases, such as measles or chicken pox, more than once.

Facing Cancer

Everyone’s immune system uses the same method to attack cancer, but the process is more complicated because cancer cells are created by the body. Because of this, the normal ways to find and fight invading cells from outside the body aren’t always effective. If the body can’t tell the difference between the tumor cells and normal cells, the tumor cells may be able to “hide” from the immune system. Use this example to illustrate this process for your patients:

Think of allergy shots given to relieve the symptoms of an airborne allergen, such as pollen or pet dander. Increasing doses of a specific allergen are injected into a person over a series of visits to the doctor, which causes the body to develop a tolerance to pollen. This type of therapy can provide temporary or permanent relief of symptoms. However, the body no longer sees the pollen as an invader, so the immune system stops attacking it. The case with cancer cells is often similar. In early stages, cancer cells may shed proteins into the body. As these proteins circulate through the bloodstream, the body begins to develop a tolerance for the cancer cells. And once that tolerance exists, the immune system may not recognize these cancer cells as a threat. Then, just like the pollen, the cancer cells may be safe from an immune system attack.

In some cases, the DNA changes (mutations) that cause the cancer may be different enough to stimulate an immune response similar to the response described for invading virus cells.  If the immune system detects the cancer, the APCs must share the information with the T cells, which are the primary players in the fight against cancer (see Figure 4).

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The MHC on APCs must connect to receptors on T cells, and the T cells must receive both Signal 1 and Signal 2 in order to become activated and multiply. If Signal 2 is not received, the response will shut down (see Figure 5, page 6). A T cell can function properly against the cancer only if it recognizes the cancer as harmful, receives the proper signals to become activated, and continues to get signals to continue the attack.Imm_System_Fig_5.jpg

Tumor cells can create cytokines, which means that cancer cells can communicate with and confuse other immune cells, allowing the cancer to take control of certain parts of the process that the body uses to regulate the immune response. So, even if the immune system recognizes the cancer, it may not be able to successfully start or maintain an attack long enough to kill the cancer cells.

The ability of T cells to become activated and attack cancer is at the heart of immunotherapy research. One specific area of research focuses on how cancer cells can trick the immune system into turning on “checkpoint pathways” early.

Checkpoint pathways are part of the system of checks and balances that allow the immune cells to evaluate the attack against the threat at multiple stages. The pathways essentially function as the “brakes” when the body determines the response is no longer needed. By using signals to confuse other immune cells into putting on the brakes, the cancer can shut down the attack before it has responded effectively and thus, the cancer cells continue to grow.

Blocking the effect of these checkpoint pathways can restore the normal function of the immune cells. Recent breakthroughs in immunotherapy research have involved two main checkpoint pathways: the CTLA-4 immune checkpoint pathway and the PD-1/PD-L1 immune checkpoint pathway (see Figure 6). 

Imm_System_Fig_6.jpgThe longer the cancer cells face a weakened immune response, the more they’re able to adapt, and the easier it is for them to manipulate immune cells inside the tumor’s microenvironment, an area in which the tumor grows. This area, or microenvironment, typically contains cancer cells, normal connective tissues that form the structure of the tumor, access to blood vessels that drive tumor growth and several cell types that contribute to tumor development.

Immune cells found in this area are often referred to as tumor-infiltrating lymphocytes (TILs). Because the tumor can control cells in this microenvironment, the tumor can trick TILs into becoming useless or even helping the tumor grow. For example, APCs may be confused by signals from tumor cells, preventing the APCs from functioning properly, and making them incapable of sounding the alarm about a threat.

In some cases, tumors can upregulate (increase) the activity of regulatory T cells inside the microenvironment. With this increased activity, regulatory T cells are actually working to reduce the immune response around the tumor by turning off the other cancer-specific T cells. It’s as if the tumor recruits the body’s own immune cells to fight off the attack, using the very processes that normally protect the body.

The longer the immune system is exposed to the tumor, the weaker the immune response becomes. Immunotherapy research focuses on identifying different ways tumors manipulate the immune system and how to reverse those processes.

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