The function of the body’s immune system deteriorates as we age, making us more susceptible to infection. Now, a study published in PNAS in February suggests it could also be a key factor in the development of cancer.
Scientists have long known that the chances of developing cancer increase dramatically with age. For decades, they’ve explained this finding based on the accumulation of genetic mutations: a single cell develops one genetic mutation, then another, and another. After five or six major changes occur in that cell, it becomes a cancer cell. Since it can take many years for these key mutations to arise in the same cell on a random basis, we are more likely to develop cancer as we get older.
But our body is also getting older at the same time. Every 16 years, our thymus gland shrinks to half its former size, producing fewer and fewer T cells, the white blood cells that fight invaders and cancer cells. Researchers at the University of Dundee in Scotland decided to look at this decline in the number of T cells. They hypothesized that if cancer cells arose at a constant rate throughout life while the immune system became less effective at recognizing and killing those aberrant cells, it would make sense that the incidence of cancer would increase with age.
To test this, the team built a mathematical model that predicted the way cancer incidence would rise based on the decline of the aging immune system. Then they applied the model to cancer incidence data collected by the U.S. National Cancer Institute, spanning over two million cases of cancer. They found that their model fit the data better, on the whole, than the well-established multiple mutation model. For certain cancers, such as chronic myeloid leukemia, their model fit extremely well, as the increase in incidence with age precisely mirrored the decline of the thymus gland and immune system. And it explained why men are more likely to get cancer than women as we age: the thymus shrinks more slowly in women than in men.
Sam Palmer, the primary author of the study, says the results suggest that only one “driver” mutation may be required for a cell to become cancerous, rather than the six or seven required with the multiple mutation model. The other mutations could be more like “passenger” mutations that are the effect of the cell being cancerous, not the cause, he says.
But this immune system model of cancer has yet to be experimentally validated by cancer biologists or doctors. Some of its assumptions may be over-simplified, says Sui Huang, a molecular and cell biologist at the Institute for Systems Biology in Seattle. “This paper brings fresh thinking, but it makes an assumption that is highly controversial, that immune surveillance protects us against cancer,” he says.
Huang points out that people who lack a thymus have less cancer, not more as the new model would predict. And people who are chronically immunosuppressed don’t have a markedly higher incidence of typical age-related cancers like breast and prostate cancers (though they have a higher risk of certain other cancers, such as non-Hodgkin lymphoma and those caused by viruses like cervical cancer). “These are paradoxes,” says Huang, “but I’m willing to accept them because I like the beauty of the work. It has a boldness to it, just seeing what happens if we put our assumptions into a rigorous mathematical framework.”
Looking at epidemiological data also has certain limitations, according to Patricia Thompson-Carino, a molecular and cell biologist at the Stony Brook School of Medicine in Stony Brook, New York. Because the authors looked at all cancer diagnoses, which are often detected by screening before there are any clinical symptoms, they may have included early tumors in the model as well. But early tumors caught this way may never have turned into a full symptomatic cancer.
The new work doesn’t upend the multiple mutations model, says Thompson-Carino. “We have very strong evidence that cells acquire multiple mutations; all our data suggests at least for highly malignant, life-threatening cancers, with very few exceptions, like leukemias, there is no evidence that there is only one driving mutation,” she says.
At the very least, the new study suggests that the immune system’s role in the development of cancer may be more important than previously suspected. What’s also exciting, says Thompson-Carino, is that it points to new potential avenues for research and treatment: looking at the immune system, specifically the thymus and its T cells, and whether we can modify their function to help protect us against cancer.