Loss of the Y Chromosome Impairs Body's Ability to Fight Cancer

According to recent Cedars-Sinai Cancer research, as men age, some of their cells lose the very feature that makes them biological males—the Y chromosome—and this loss impairs the body’s ability to fight cancer.

The research, published today in the prestigious scientific journal Nature, discovered that Y chromosome deletion aids cancer cells in evading the body’s immune system. This natural effect of aging in males causes aggressive bladder cancer, but it also makes the disease more vulnerable—and responsive—to a routine treatment known as immune checkpoint inhibitors.

Based on their findings, the researchers are developing a test for Y chromosome loss in tumors, with the goal of assisting clinicians in tailoring immune checkpoint inhibitor treatment for male patients with bladder cancer.

This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer.”

Dan Theodorescu, Study Corresponding Author and Director, Cedars-Sinai Cancer

Dan Theodorescu, who is the PHASE ONE Distinguished Chair and corresponding author of the publication, initiated the research.

Dan Theodorescu adds, “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

Johanna Schafer, a Postdoctoral Fellow, and Zihai Li, MD, Ph.D., a Medical Oncologist and Immunologist at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, were also key contributors to the work.

Each cell in humans generally contains one pair of sex chromosomes; men have one X and one Y chromosome, while women have two X chromosomes. Loss of the Y chromosome has been reported in various cancer types in men, including 10–40% of bladder cancers. The loss of the Y chromosome has also been linked to heart disease and Alzheimer’s disease.

The blueprints for several genes are found on the Y chromosome. The researchers created a scoring system to quantify Y chromosome deletion in cancers based on how these genes are expressed in normal cells in the bladder lining.

The researchers then examined data from two groups of men. One group was identified with muscle invasive bladder cancer and had their bladders removed, but they were not given an immune checkpoint inhibitor.

The other group took part in a clinical trial and was given an immune checkpoint inhibitor. They discovered that patients with Y chromosome loss had an even worse prognosis in the first group and much improved overall survival rates in the latter.

To figure out why this happens, the researchers analyzed the growth rates of bladder cancer cells from laboratory mice.

The researchers generated cancer cells in a dish that was not exposed to immune cells. The diseased cells were also grown in mice lacking a type of immune cell known as T-cells. Tumors with and without the Y chromosome grew at the same pace in both cases.

Cancers without the Y chromosome grew considerably quicker in mice with intact immune systems than tumors with the entire Y chromosome.

The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer. These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”

Dan Theodorescu, Study Corresponding Author and Director, Cedars-Sinai Cancer

Based on their findings from human patients and laboratory mice, Theodorescu and his colleagues determined that cancers lacking the Y chromosome were not only more aggressive but also more vulnerable and responsive to immune checkpoint inhibitors. One of the two mainstay bladder cancer treatments accessible to patients today, this therapy reverses T-cell exhaustion and permits the body’s immune system to combat the tumor.

Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors.”

Hany Abdel-Hafiz, Associate Professor, Cedars-Sinai Cancer

Hany Abdel-Hafiz is also the co-first author of the study with Schafer and Xingyu Chen, a research bioinformatician at Cedars-Sinai.

According to preliminary research that has yet to be published, Y chromosome deletion makes prostate tumors more aggressive, according to Theodorescu.

Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs. This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

Shlomo Melmed, Executive Vice President, Academic Affairs, Cedars-Sinai Cancer

Shlomo Melmed is also the Dean of the Medical Faculty at Cedars-Sinai.

More research is needed to help researchers comprehend the genetic link between Y chromosome loss and T-cell exhaustion.

Dan Theodorescu adds, “If we could understand those mechanics, we could prevent T-cell exhaustion. T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”

Although women lack a Y chromosome, Theodorescu believes these findings may have ramifications for them as well. On the X chromosome, the Y chromosome contains a set of related genes known as paralogue genes, which may play a function in both men and women. More research is required to establish what that role might be.

Dan Theodorescu concludes, “Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology. The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”