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Loss of Y Chromosome May Help Bladder Cancers Grow

Computer-generated representation of chromosomes.
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A study, using data from both humans and mice, has shown that loss of the Y chromosome – a common part of the male aging process – may allow bladder cancer to escape the immune system, but may also make tumors more sensitive to immunotherapy. The research is published in Nature.

Sex differences in cancer

Human cells usually contain a pair of sex chromosomes – known as X and Y – that determine our biological sex. Males typically have one X and one Y, whereas females typically have two X chromosomes.

However, Y chromosomes can be gradually lost from male cells as they age. This has been linked to cardiovascular disease and Alzheimer’s disease as well as several types of cancer. Y chromosome loss is found in approximately 10–40% of bladder cancers, but it is unclear how this can affect outcomes for affected patients.

Therefore, researchers from Cedars-Sinai Medical Center used data from both patients and laboratory models to investigate how Y chromosome loss may relate to the biology and treatment of these cancers.

Exhausting immune cells

Firstly, the researchers created a scoring system for bladder cancers, measuring Y chromosome loss in the cells that line the bladder based on the expression of Y chromosome genes.

They compared these measurements from data obtained from two groups of men – the first who had advanced bladder cancer, had their bladders removed and had not received immunotherapy, versus a second group with advanced bladder cancer who received an immune checkpoint inhibitor (a type of immunotherapy) as part of a clinical trial.

What is immunotherapy?

Immunotherapy helps the body’s own immune system to find and fight cancers. Immune checkpoint inhibitors are an important part of immunotherapy and help release the “brake” that cancer cells can manipulate and apply to T cells, allowing them to fight the tumor.

Patients with Y chromosome loss had a poorer prognosis in the first group and much better overall survival rates in the second group.

To find out why this was happening, the researchers turned to laboratory mice. When bladder cancer cells with and without Y chromosome loss were grown in mice that lacked T cells – a type of immune cell – their tumors grew at a similar rate. However, when they were grown in mice with T cells, tumors lacking the Y chromosome grew at a much faster pace.

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“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,” said Prof. Dan Theodorescu, senior author of the study and director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai. “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.”

Using data from both the mouse and human studies, the researchers conclude that, despite growing more aggressively, these tumors were more vulnerable to immune checkpoint inhibitors. These drugs are one of the two mainstay treatments used for bladder cancers today, and help to reverse T-cell exhaustion and take the fight back to the cancer cells.

“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,” said Dr. Shlomo Melmed, executive vice president of Academic Affairs and dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

Additional implications?

Theodorescu said these findings could have implications for women, as well. A set of genes related to those found on the Y chromosome are also found on the X chromosome – these may play a role in both men and women, though further research is required.

“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,” said Theodorescu. “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.”

Reference: Abdel-Hafiz HA, Schafer JM, Chen X, et al. Y chromosome loss in cancer drives growth by evasion of adaptive immunity. Nature. 2023. doi: 10.1038/s41586-023-06234-x 

This article is a rework of a press release issued by Cedars-Sinai Medical Center. Material has been edited for length and content.