How does the immune system work? When it comes to cancer, it's complicated

immune system
The immune system is a complex apparatus that both protects the body and, in some cases, helps cancer destroy it.

Every second of every minute of every day, a battle of good and evil goes on inside your body. The good is the immune system, armies of cells designed to defend the body from illness and infection. The evil comes in the form of pathogens, viruses, bacteria and mutated cells that are programmed to do harm. When it comes to cancer, the good guys don’t always win. But new immunotherapy treatments, emerging technologies and ongoing research are giving doctors more tools to help the immune system do the job it was meant to: fight back against threats like cancer. More developments are coming online as cancer researchers learn more about how the immune system works, how cancer hides from immune cells and how some immune cells actually help cancer grow. What they are finding is that the immune system is a complex apparatus that both protects the body and, in some cases, helps cancer destroy it.

"The immune system is critical in fighting cancer," says Stephen Lynch, MD, Primary Care and Intake Physician at our hospital near Phoenix. "We have an immune system that is designed to recognize native and non-native cells that can harm us. The problem is, it doesn't always work. Other times, it works against us."

The immune system is an efficient and powerful biological machine. It protects us from millions of germs and fights off viruses and infections. So powerful are its responses that they may cause fevers, aches and pains, inflammation and swelling. "It's because your immune system is ramping up—it's doing what it's supposed to do," Dr. Lynch says. And what it does is more than fight off disease. Researchers at Northwestern University have concluded that immune cells known as macrophages stimulate cells in the heart muscle, helping to keep the heart pumping and maintain a steady beat. Swedish researchers have also found evidence that immune cells clear out dead brain cells after a stroke and secrete substances that may allow the brain to repair damage. At the same time, though, scientists are learning how cancer cells not only evade the immune system’s defenses, but actually use immune cells to facilitate their attack on the body.

Military precision

In military terms, the immune system has two divisions: innate and acquired. Within each division are regiments of different cells that perform specific immune functions. Innate immunity is the body’s first line of defense. These immune cells are programmed to attack cells they sense as a threat to the host. "Innate immune cells kill first and ask questions later," Dr. Jeffrey Weber, deputy director of the Perlmutter Cancer Center in New York City, quipped in a video lecture about the immune system. Among the cells in the innate immune system are:

Macrophages: Named for the Greek words that mean “big eaters,” these long-limbed cells are true to their moniker. They are voracious, using flexible tendrils to snag and attack their targets.

Neutrophils: These short-lived cells are the first line of defense against infection. They kill bacteria, then die, forming pus.

Dendritic cells: These are the innate immune system's traffic cops, directing T-cells and B-cells to their targets.

Mast cells and basophils: They produce histamines that help the immune system attack allergens.

Natural killer (NK) cells: These rapid-response cells attack viruses and may also be aggressive in attacking cancerous and pre-cancerous cells.

The acquired immune system—also called adaptive immunity—is more sophisticated and takes longer to develop a plan of attack. The cells of adaptive immunity are:

B-cells: They develop and mature in the bone marrow and make proteins called antibodies that fight viruses and bacteria.  

T-cells: They also form in bone marrow, but mature in the thymus. There are two main types of T-cells: helper T-cells that stimulate B-cells to make antibodies, and killer T-cells that attack cells directly.

Adaptive immune cells target viruses or bacteria, using information delivered from dendritic cells and other innate cells, and they store information about these pathogens so they can recognize and target them again should they launch another attack.

The tipping point

But if the immune system is so strong and sophisticated, why does it fail so often in fighting cancer? The short answer: because the cancer overpowers it. "I tell my patients that if we didn’t have an immune system, we'd all get cancer," says Alan Tan, MD, Medical Director of Hematology and Immunotherapy and Medical Oncologist and Hematologist at our hospital near Phoenix. "There's a fine balance between the burden of cell mutation and how well your immune system can fight it off. It is always alert to threats. It's when the immune system is overwhelmed by a tumor that it fails to identify and respond to the threat."

Indeed, it is possible, even likely, that your immune system may regularly fight off cancer or pre-cancer on a regular basis without you even knowing it. "We all have a mechanism to filter out a small amount of cancer cells to prevent us from having visible cancer in the body," Dr. Tan says. "Over time, that balance becomes lost."

The tipping point at which cancer begins to overwhelm the immune system is not always known. "There are lots of different reasons why that might happen," Dr. Lynch says. "Some of it has to do with the DNA of the tumor. Some of it has to do with the aggressiveness of the cancer." But research has shown that cancer cells exert tremendous sway over some innate and adaptive immune cells and recruit them to help cancer grow and travel. Researchers at Georgia Cancer Center at Augusta University report finding evidence that cancer cells use immature immune cells called myeloid-derived suppressive cells (MDSCs) to metastasize. Using deceptive signaling, cancer cells stifle the growth of MDSCs and use them to help tumors spread. "These cells are essential to successful cancer metastasis," Georgia Cancer Center’s Dr. Hasan Korkaya told Science Daily. "There is a very intricate balance in the immune system that is usually anti-tumorigenic, meaning it eliminates tumors, but in some cases, if this balance is altered, these cells may actually help tumors grow and develop into full-blown metastatic disease."

Jumpstarting the immune system

An article in Nature describes how tumor-associated macrophages (TAMs) help breast tumors form. Macrophages are often found in large numbers in some breast tumors. While they are capable of attacking cancer cells, "macrophages within mammary tumors are inadvertently licensed to promote tumor growth and metastasis," the Nature article says. Researchers and students at Albert Einstein School of Medicine report capturing this process on video. The film shows macrophages and breast cancer cells in mice working side by side to help the cancer cells break into the bloodstream.

Research suggests that an immunotherapy drug that targets TAMs and other innate cells may stimulate the immune system to attack tumors. Doctors at the Dana-Farber Cancer Institute are researching a compound, called TMP195, that is designed to re-activate TAMs to attack cancer cells. The research has shown that the process shrinks breast cancer tumors in mice. In 2015, the FDA approved elotuzumab (Empliciti), considered an immune-stimulating drug, to treat multiple myeloma. "This drug not only targets multiple myeloma cells, but it enhances natural killer cells," Dr. Tan says. "Myeloma cells can suppress natural killer cells. But as the myeloma cell population decreases, it increases the NK cells in number and function."

While researchers continue to study immunotherapy drugs that recharge innate immune cells, substantial progress has been made in developing drugs that activate T-cells, the adaptive immune system's stalwart. In August, the FDA approved the first adoptive cell transfer therapy that uses modified immune cells called chimeric antigen receptor (CAR) T-cells. These cells use a patient’s own T-cells that are modified with a gene, reproduced in the lab by the billions and then infused back into the patient, to attack specific cancer cells. The therapy has been approved for young patients with acute lymphoblastic leukemia, and ongoing research is exploring whether it may be used to treat other liquid cancers. Also, checkpoint inhibitors, first approved for melanoma in 2011, are now used to treat eight cancers and, in a first-of-its-kind FDA approval, cancers that have a specific genetic mutation.

Unlike chemotherapy and radiation therapy, which kill cancer cells directly, immunotherapy drugs don't attack cancer cells, but rather kick-start the body's powerful immune system. "The immune system is absolutely critical in fighting cancer," Dr. Lynch says. "Immunotherapy is not going in there and killing the cancer cells. It's simply pulling the disguise off the cancer cell that's trying to hide and allowing the immune system to recognize it and do the job it’s designed to do."

Learn more about immunotherapy.