Loss of Y chromosome in men, with age, favors cancer growth

As they age, some cells of the body in men lose the Y chromosome (the element that makes them biologically male), and this loss allows the cells of the cancer can evade the body’s immune system and grow easily.

This is the main conclusion of an investigation from the Cedars-Sinai Cancer Center (Los Angeles, California) published this Wednesday in Nature.

The study found that this common effect of aging in men leads to aggressive bladder cancer, but also makes the disease more responsive to an immunotherapy treatment called ‘immune checkpoint inhibitors’.

Researchers are already developing a test to detect loss of the Y chromosome in tumors to help doctors tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.

“This study establishes for the first time a never-before-established connection between Y-chromosome loss and the immune system’s response to cancer,” said Dan Theodorescu, director of Cedars-Sinai Cancer Center.

“We discovered that the loss of the Y chromosome allows bladder cancer cells to evade the immune system and grow very aggressively,” says Dan Theodorescu, who led the research.

MEN AND WOMEN HAVE DIFFERENT CHROMOSOMES

In humans, each cell has a pair of sex chromosomes: males have one X and one Y chromosome, and females have two X chromosomes.

In men, the loss of the Y chromosome has been linked to several types of cancer, especially bladder cancer, but this loss is also associated with heart disease and Alzheimer’s disease.

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells lining the bladder, the researchers developed a scoring system to measure Y chromosome loss in cancers.

Next, they reviewed data from two groups of men, one with bladder cancer who had his bladder removed and was not treated with immune checkpoint inhibitors, and another who participated in a clinical trial and received treatment with this immunotherapy treatment.

They found that patients with Y chromosome loss had a worse prognosis in the first group and much better overall survival rates in the second.

To find out why this was happening, they compared the growth rates of bladder cancer cells with cells from laboratory mice.

The team grew tumor cells that were not exposed to immune cells and also grew diseased cells in mice lacking immune cells called T cells. In both cases, the tumors with and without the Y chromosome grew at the same rate.

However, in mice with intact immune systems, tumors lacking the Y chromosome grew at a much faster rate than tumors with the intact Y chromosome.

“These results imply that when cells lose the Y chromosome, they deplete T cells. And without T cells to fight the cancer, the tumor grows aggressively,” concludes Theodorescu.

The team also concluded that tumors lacking the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors.

This therapy, one of the two main treatments available for bladder cancer, reverses the depletion of T cells and enables the body’s immune system to fight the cancer.

The researchers believe that the loss of the Y chromosome is an adaptive strategy of tumor cells to evade the immune system and survive in multiple organs, although they acknowledge that more work is needed to understand the genetic connection between the loss of the Y chromosome and the depletion of T cells.

Prepared with information from EFE