WEDNESDAY, June 21, 2023 (HealthDay News) — It’s common knowledge that loss is part of male aging — lack of hair, lack of muscle tone, lack of vision or hearing.
But men growing older also start losing the very thing that makes them biological males, their Y chromosome, and that may leave them more vulnerable to cancer, a brand new study says.
The lack of the Y chromosome can assist cancer cells evade detection by the body’s immune system, in response to researchers from Cedars-Sinai Medical Center, in Los Angeles.
Specifically, it leads to more aggressive bladder cancer amongst men, the study authors reported June 21 within the journal Nature.
“This study for the primary time makes a connection that has never been made before between lack of the Y chromosome and the immune system’s response to cancer,” said researcher Dr. Dan Theodorescu, director of Cedars-Sinai Cancer.
“We discovered that lack of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively,” Theodorescu said in a medical center news release.
It’s not all bad news, nevertheless. Bladder cancers driven by the lack of the Y chromosome also were more vulnerable to immune checkpoint inhibitors, that are drugs that enhance the body’s ability to focus on and destroy tumor cells, the researchers explained.
Each human cell normally has one pair of sex chromosomes. Men’s cells have one X and one Y chromosome, while women have two X chromosomes.
Y may disappear with aging
Nevertheless, aging men can lose the Y chromosome from some cells during normal cell division.
Investigators have found the Y chromosome missing from some white blood cells in about 40% of 70-year-old men and 57% of 93-year-olds, in response to Montefiore Medical Center in Latest York City. In some older men, greater than 4 out of 5 white blood cells can lack a Y chromosome.
Lack of the Y chromosome has been observed in several cancer types in men, including 10% to 40% of bladder cancers, Cedars-Sinai researchers said in background notes. It has also been related to heart disease and Alzheimer’s disease.
The Y chromosome incorporates the blueprints for certain genes. The Cedars-Sinai research team studied the best way these genes are expressed in normal cells within the bladder lining, and used that to develop a scoring system that would measure the lack of the Y chromosome in bladder cancer.
The investigators then reviewed data on two groups of men with invasive bladder cancer. One group had their bladders removed but weren’t treated with an immune checkpoint inhibitor, while the opposite group received the immunotherapy.
Patients with lack of the Y chromosome had a poorer prognosis in the primary group and significantly better overall survival rates within the latter, the findings showed.
To work out why this happens, the team performed lab experiments involving bladder cancer cells in mice.
The researchers found that mouse tumor cells lacking the Y chromosome grew at a much faster rate than did tumors with the intact Y chromosome.
Nevertheless, this only happened in mice with intact immune systems. In mice missing a form of immune cell called T-cells, tumors with and without the Y chromosome grew at the identical rate.
“The undeniable fact that we only see a difference in growth rate when the immune system is in play is the important thing to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “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.”
A silver lining
Based on all of this, Theodorescu and his colleagues also concluded that tumors missing the Y chromosome, while more aggressive, were also more vulnerable and attentive to immune checkpoint inhibitors.
This immunotherapy, one in every of the 2 mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and prompts the immune system to fight the cancer.
“Fortunately, this aggressive cancer has an Achilles’ heel, in that it’s more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said co-lead researcher Hany Abdel-Hafiz, an associate professor at Cedars-Sinai Cancer.
Preliminary data not yet published shows that lack of the Y chromosome may make prostate cancers more aggressive, Theodorescu said.
“Our investigators postulate that lack of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, dean of the medical faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and will have far-reaching implications for cancer treatment going forward.”
Further research is required to higher understand the genetic connection between lack of the Y chromosome and T-cell exhaustion, the study authors noted.
“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion could be partially reversed with checkpoint inhibitors, but when we could stop it from happening in the primary place, there may be much potential to enhance outcomes for patients.”
While women do not need a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome incorporates a set of related genes on the X chromosome, and these might play a job in each ladies and men.
“Awareness of the importance of Y chromosome loss will stimulate discussions concerning the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The basic recent knowledge we offer here may explain why certain cancers are worse in either men or women, and the way best to treat them. It also illustrates that the Y chromosome does greater than determine human biologic sex.”
More information
The U.S. National Cancer Institute has more about immune checkpoint inhibitors.
SOURCE: Cedars-Sinai Medical Center, news release, June 21, 2023