The Immune System and Cancer

Guest Post by William G. Nelson, MD, PhD
Editor-in-Chief, Cancer Today

The immune system protects against bacteria, viruses, and fungi that would invade and spread throughout the body and potentially threaten life. To fight these invaders, the immune system must distinguish between “self”—normal cells and tissues—and “nonself”—threats to the body. New insights hint that immune cells can recognize cancer cells as “nonself,” and if unleashed, can destroy them.

Cancer cells arise from normal cells by acquiring defects in genes. These acquired gene defects are passed along at every cancer cell division. By the time a cancer is diagnosed, there may be as many as a billion cancer cells containing these defects. The defective genes direct the production of abnormal proteins that immune cells appear to see when they recognize cancer cells as “nonself.” Sometimes even a single abnormal protein is enough for a cell to appear foreign to the immune system.

In 1966, cancer researcher Henry T. Lynch reported on two large families with 78 cancers that affected many family members across several generations. Family members who inherited this vulnerability to cancer seemed to have a reduced ability to repair errors in DNA, called DNA mismatches, that arise when DNA sequences are copied during cell division. This vulnerability is now called hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome.

Although in HNPCC, each mismatch mistake rarely causes a gene defect that can fuel cancer, the sheer quantity of mismatch errors increases the chance that cancers will appear in people with the condition. Not surprisingly, the cancers that arise among people with HNPCC have large numbers of gene defects, in addition to those that created the cancer, often leading to hundreds to thousands of abnormal proteins.

If immune cells can recognize a cell containing a single abnormal protein as foreign, they must definitely see HNPCC cancer cells with several hundred abnormal proteins as foreign. So how do HNPCC cancers avoid being attacked by the immune system?

One way cancer cells evade immune destruction is by delivering signals that hold immune cells in check. New anti-cancer treatments have attempted to stop these immune checkpoint signals. The drugs ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) unshackle anti-cancer immune responses, leading to striking, and often lasting, benefits for some patients with certain cancers. The excitement generated by this treatment approach has led to widespread testing of immune checkpoint blockers, alone and in various combinations, against different cancer types. So far, the outcomes have been mixed. Some patients show near-miraculous results and others realize few benefits.

Dung Le and her colleagues, in reporting the outcome of treating HNPCC cancers with pembrolizumab in the June 25, 2015, New England Journal of Medicine, may have partly solved the enigma of why responses to immune checkpoint blockers have been so diverse. Among colorectal cancer patients receiving pembrolizumab, the benefits seen in patients with HNPCC cancers greatly exceeded those for non-HNPCC cancer patients. The reason may be the higher number of abnormal proteins in the HNPCC colorectal cancers compared with other colorectal cancers—more than 20 times the number.

This is a stunning treatment advance for those with HNPCC cancer. Hopefully, immune responses for non-HNPCC cancers—the majority of cases—can also be better understood. In this way, the immune system can be helped not only to recognize all cancer cells as “nonself,” but to destroy them.

Photo by Joe Rubino.
Photo by Joe Rubino.

William G. Nelson, MD, PhD, is the editor-in-chief of Cancer Today, the quarterly magazine for cancer patients, survivors, and caregivers published by the American Association for Cancer Research. Dr. Nelson is the Marion I. Knott professor of oncology and director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. You can read his complete column in the fall 2015 issue of Cancer Today.

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