Why colorectal cancer breaks the immune system’s rules

In most solid cancers, having a large number of regulatory T cells (or Treg cells) is linked to worse outcomes for patients. These immune cells normally act as brakes on the immune system, which means they can weaken the body's ability to attack cancer.

Colorectal cancer stands out as a rare and confusing exception. In this disease, tumors with more Treg cells are often associated with longer patient survival. For years, researchers did not understand why this pattern is so different from what is seen in other cancers.

A new study from the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center (MSK) now offers a clear explanation. The findings could help improve immunotherapy for most people with colorectal cancer. They may also apply to cancers that develop in tissues like the skin and the lining of the stomach, mouth, and throat.

The key discovery is that Treg cells are not all the same. According to results published in the scientific journal Immunity, what matters most is not just how many Treg cells are present, but which kind they are.

"Instead of the regulatory T cells promoting tumor growth, as they do in most cancers, in colorectal cancer we discovered there are actually two distinct subtypes of Treg cells that play opposing roles," says Alexander Rudensky, PhD, a senior author of the study and chair of the Immunology Program at MSK. "One restrains tumor growth, while the other fuels it. It's these beneficial Treg cells that make the difference, and this underscores the need for selective approaches."

The study builds on more than 20 years of research by Dr. Rudensky, a leading expert on regulatory T cells. His research helped establish that Treg cells maintain "immune tolerance." This means they help the immune system tell the difference between harmful threats and harmless targets. They prevent unnecessary attacks on the body's own cells, helpful microbes, and everyday foods.