Immunotherapy

The immune system and how it works

Immunotherapy uses the same natural defenses your body uses every day to fight infection. However, your body’s immune system isn’t always able to handle something as intense as cancer on its own, so doctors build on the healing capabilities of your immune system with immunotherapy.

Understanding the immune system

The immune system is the body’s natural defense against infection and disease, protecting the body from harmful substances, such as bacteria, viruses (also called germs) and cancer. The cells of the immune system continuously flow through the body, looking for germs that may be invading the body. The immune system recognizes invaders by their antigens, which are proteins on the surface of the invading cells (see Figure 1).

                                           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. People carry self-antigens on normal cells, such as liver, colon and thyroid cells. Cells with self-antigens are typically not a threat. Invading germs, however, do not come from within the body, so they do not carry self-antigens. Instead, they carry “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.

Your immune system is always working to keep your body free from infection. Your skin is your immune system’s first barrier. When you skin your knee, you break that barrier, and harmful substances can easily enter the body (see Figure 2). As soon as this happens, immune cells in the injured tissue begin to respond and also call other immune cells that have been circulating in your body to gather at the site and release cytokines to call even more immune cells to help defend the body against invasion. The immune cells recognize any bacteria or foreign substances as invaders. Immune cells, also called natural killer cells, begin to destroy the invaders in 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.

                 Figure 2

At the same time, other immune cells called dendritic cells start to “eat” the invaders and their nonself-antigens. This process causes the dendritic cells to transform into antigen-presenting cells (APCs). These APCs expose the invader 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 that help identify and stop the invading bacteria cells. Viruses, unlike bacteria, like to hide inside normal cells and may be harder for the immune system to recognize.

T-cells 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.

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 starts.

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 T-cell then multiplies to develop an army of T-cells that is equipped with the necessary weapons 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.

                                   Figure 3

Other T-cells may become memory T-cells. Memory T-cells can stay alive for years, continuing to fight off the same invading cells. 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

Your immune system basically attacks cancer in the same way, 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 tumor cells and normal cells, the tumor cells may be able to “hide” from the immune system (see Tolerating Cancer below).

Sometimes, the DNA abnormalities (mutations) that cause 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 show cancer cell materials to T-cells, the primary players in the fight against cancer. The MHC on APCs must connect to receptors on T-cells, and the T-cells must receive both Signal 1 and Signal 2 to become activated and multiply. If Signal 2 is not received, the response will shut down. 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.

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.

Researchers continue to investigate immunotherapy strategies, and the ability of T-cells to become activated and attack cancer is at the heart of that research. One 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 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 allow the cancer cells to continue to grow. Blocking the effect of these checkpoint pathways can restore the normal function of the immune cells.

The 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 location (sometimes called the microenvironment). This area 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 the microenvironment, the tumor can trick TILs into becoming useless or even helping the tumor grow. For example, APCs in the tumor microenvironment 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 area. With this increased activity, regulatory T-cells are actually working to reduce the immune response around the tumor by turning off the other cancer-fighting 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.

 

Tolerating Cancer: How Cancer Cells Hide

To understand how cancer cells are able to evade detection, think of suffering from a pollen allergy. Your doctor may give you allergy shots to relieve the symptoms, such as sneezing and watery eyes. You receive increasing doses of a specific allergen over a series of visits to the doctor, which causes your body to develop a tolerance to pollen. This type of therapy can provide temporary or permanent relief of symptoms. Your body no longer sees the pollen as an invader, so your immune system stops attacking it. This situation is similar to what can happen with cancer cells.

In early stages, cancer cells may shed proteins into the body. As these proteins circulate through the bloodstream, your body begins to develop a tolerance for the cancer cells. Just like your body no longer sees pollen as an invader, 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.

Immunotherapy seeks to reverse this tolerance, to once again identify the cancer cells as a threat and a target for destruction.

 

Additional Resources

 

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