Immunotherapy

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A Brief Guide to the Immune System

The human immune system is a fabulously complex array of defenses that evolved to protect our bodies from foreign invaders. Infectious organisms such as bacteria, fungi, parasites, and viruses all have specific molecular targets called “antigens,” which are recognized by the immune system. But allergens (like pollen) and foreign proteins (from improperly matched transfusions, transplants, or biological medicines) can also serve as antigens that trigger an immune response.

Why Cancer Fools the Immune System

Cancer is a genetic disease. It occurs when damaged DNA sends out faulty signals along one or more biomolecular pathways, causing tumor cells to grow out of control. Because the invasion of tumor cells is home grown rather than foreign, an immune response is often not effectively triggered. In some cases, despite antigens present on growing tumors, the immune response is not strong enough to destroy the cancer. In addition, cancers have developed defenses of their own. For example, some cancers have the ability to secrete the precise chemicals that signal our bodies to shut down the immune response.

To further complicate matters, the immune system remains vigilant if we attempt to introduce healthy tissue from another person that is intended to help patients fight their cancer. Treatments such as bone marrow transplants have to pay strict attention to tissue compatibility. Otherwise the body will mount an immune response—in effect, rejecting the cure while protecting the disease.

Re-Educating the Immune System with Immunotherapy

Because the challenges of cancer are so diverse, researchers have attacked the problem on a number of fronts. As a result, immunotherapy is a collection of techniques that use different components of the patient’s immune system to fight cancer. Some are designed to get the body to recognize cancer tissue as foreign. Others try to increase the strength of the natural immune response. And still others work to interfere with the molecular pathways that cancer cells have taken over to sustain themselves.

Most of the immunotherapy techniques that patients are likely to encounter as approved therapies or in clinical trials involve the body’s “adaptive” immune responses mediated by white blood cells called lymphocytes. To begin with, we’ll focus on lymphocytes, including their genesis in the bone marrow; their development into B-cells, which produce antibodies; the subtypes and functions of T-cells; and the function of immune-system proteins called cytokines.

Bone Marrow is the White Blood Cell Factory

All white blood cells originate in the bone marrow. They all start as hematopoietic (blood-forming) stem cells and then differentiate into cells with highly specialized functions. The two primary types of lymphocytes are B-cells and T-cells. B-cells mature and become differentiated in the bone marrow. T-cells leave the bone marrow to develop in a specialized organ called the thymus—located behind the breastbone.

B-Cells Produce Antibodies

If a B-cell detects an antigen, its function is to mass-produce an antibody—a secreted receptor protein precisely configured to bind with the specific target antigen. The activated B-cell receives a battlefield promotion: It transforms itself into a giant plasma cell that churns out clones of the antibody at a fantastic rate—as many as 10 million per hour.

How Antibodies Work

Interestingly, this army of millions of identical antibodies doesn’t actually kill the invading organisms. In fact, the antibodies are more of a targeting mechanism. Each antibody is a specialized receptor that binds an enemy; this serves as a signal directing a protein complex called the “complement cascade” to come finish the job. Antibodies can also be bound by phagocytic cells that ingest and destroy the microbial invader in a process called antibody directed cellular cytotoxicity (ADCC).

Many Types of T-Cells do Different Jobs

The operation of T-cells in detecting antigens is even more complex. Here’s how it works: We’ve already seen that B-cell receptors (antibodies) recognize foreign antigen targets directly and bind to them. T-cells receptors cannot bind directly; they require help. When microbes invade, they produce foreign proteins; tumor cells produce abnormal proteins. In either case, protein antigens link to a cell surface protein called a major histocompatibility complex (MHC) marker. These MHC proteins are also known as a patient’s “tissue type.” The MHC protein works more or less like an adapter that’s needed to complete the bond between the infected cell or tumor cell and the T-cell receptor.

The two main types of T-cells are cytotoxic T-cells (or CD8+ T-cells) and helper T-cells (or CD4+ T-cells). Cytotoxic T-cells kill target cells that are expressing an antigen recognized by the T-cell. When helper T-cells recognize a target antigen, they secrete cytokine molecules that help to amplify T-cell responses.

How T-Cells Kill Antigens

Cytotoxic T-cells contain “granules” filled with toxins. When the binding process is complete, they inject the granules into the target cells, killing them instantly.

Natural killer (NK) cells are another lymphocyte subset (different from B-cells and T-cells) that can kill infected or abnormal cells. In addition to T-cells, natural killer cells may also play a role in anti-tumor immune responses. NK cells don’t express T-cell receptors, using a different collection of cell surface receptor molecules to identify target cells.

Cytokines Carry the Messages

The immune system’s activity is so complex that it needs to be properly organized. How do these molecules and proteins “know” that they need to come together to activate each other or unlock a biochemical reaction? The answer is—you guessed it—another complex set of proteins called cytokines.

Cytokines carry messages between different types of white cells reacting to target antigens. They are secreted by both B-cells and T-cells for a variety of purposes. Cytokines can recruit many other immune cells and help to coordinate the field of action. Cytokines encourage the growth and activation of immune cells, direct cellular traffic, and can even exert a direct toxic effect and destroy target cells--including cancer cells.

Cytokines have been tested therapeutically to accelerate the immune system’s response to cancer. The two types of cytokines that are FDA-approved treatments for select cancers that patients are likely to encounter are called Interferon-alfa and Interleukin-2.

Online Resources

For more detailed information about the immune system, consult the immune system sections on the National Cancer Institute website and the National Institute of Allergy and Infectious Diseases website.