As men age, some of their cells lose their Y chromosome, which is essential for making them biological males. A new study by Cedars-Sinai Cancer researchers has now found that this loss of the Y chromosome (LOY)—a common consequence of the aging process— hampers the body’s ability to fight cancer, by promoting T-cell exhaustion and helping cancer cells evade the body’s immune system.

The team’s research, reported in Nature, showed that loss of the Y chromosome is associated with more aggressive bladder cancer, but somehow also renders the disease more vulnerable—and responsive—to immunotherapy using immune checkpoint inhibitors. Based on the findings, investigators are developing a test for LOY in tumors, with a view to helping clinicians tailor 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,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, the PHASE ONE distinguished chair, and corresponding author of the publication, who initiated the research. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

Theodorescu and colleagues reported on their study in Nature, in a paper titled “Y chromosome loss in cancer drives growth by evasion of adaptive immunity,” in which they concluded, “Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. Results may explain why certain cancers are worse in men or women, and how best to treat them, while illustrating that the Y chromosome does more than determine human biologic sex.”

Lead collaborators on the study included postdoctoral fellow Johanna Schafer, PhD, and Zihai Li, MD, PhD, medical oncologist and immunologist, who are both at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute.

In humans, each cell normally has one pair of sex chromosomes. Males have one X and one Y chromosome, while females have two X chromosomes. In men, loss of the Y chromosome has been observed in several cancer types, including 10–40% of bladder cancers, although, the team wrote, “its clinical and biological significance is unknown.” Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease. “Recent studies, aided by advances in sequencing technologies and CRISPR-mediated knockout of the entire Y chromosome, have begun to characterize the function of the Y chromosome in a variety of physiological contexts,” the researchers continued. “Given that bladder cancer is the fourth most common cancer in men and that LOY occurs in up to 40% of cases of bladder cancer, regardless of grade and stage, the understanding of how LOY contributes to the poor prognoses for bladder cancer in men is an unmet medical need and a major biological question.”

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, the investigators developed a scoring system to measure loss of the Y chromosome in cancers. They then reviewed data on two groups of men. One group had muscle-invasive bladder cancer (MIBC) and had their bladders removed, but were not treated with an immune checkpoint inhibitor. The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor. The study results indicated that patients with tumor LOY had poorer prognosis in the first group and much better overall survival rates in the latter. “Notably, decreased individual expression of four Y chromosome genes (KDM5D, UTY (also known as KDM6C), TBL1Y, and ZFY) was also associated with a poor prognosis,” they noted.

To determine why low Y chromosome bladder cancer is more aggressive, the investigators next compared growth rates of bladder cancer cells from laboratory mice. “… we assessed Y chromosome gene expression in MB49, a well-studied mouse bladder cancer cell line that has been shown to naturally lose the Y chromosome,” they wrote.

The investigators grew cancer cells without exposing them to immune cells. The team also grew the diseased cells in mice that were missing T cells. In both cases, tumors with and without the Y chromosome grew at the same rate. Conversely, in mice with intact immune systems, tumors lacking the Y chromosome grew at a much faster rate than tumors with the intact Y chromosome. “Y-positive (Y+) and Y-negative (Y–) tumors grew similarly in vitro, whereas Y− tumors were more aggressive than Y+ tumors in immune-competent hosts in a T cell-dependent manner,” the team noted.

“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,” 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.”

Moreover, the team pointed out, “Of the three genes shared between humans and MB49 cells, low expression of KDM5D and UTY were the only human genes whose loss of expression was associated with an unfavorable prognosis in human bladder cancer.” Commenting on combined data, they suggested, “Further, identification of KDM5D or UTY loss in human tumors has the potential to be a useful prognostic factor in determining the clinical aggressiveness of bladder cancer.”

Based on results from their studies in human patients and laboratory mice, Theodorescu and his team also concluded that tumors missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint blockade (ICB). This type of immunotherapy, including anti-PD-1/PD-L1 treatment, is a mainstay bladder cancer treatment available to patients today, and reverses T-cell exhaustion, to allow the body’s immune system to better fight the cancer. “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,” said Hany Abdel-Hafiz, PhD, associate professor at Cedars-Sinai Cancer and co-first author of the study with Schafer and Xingyu Chen, a research bioinformatician at Cedars-Sinai.

The authors continued, “In essence, we found that LOY tumors were able to evade adaptive immunity by promoting CD8+ T cell exhaustion. In so doing, LOY tumors were also more responsive to anti-PD-1 ICB because the primary mode of ICB is driving T-cell differentiation from exhaustion to effector function.”

Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion. “If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “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.”

The authors further noted, “Since age-related LOY is widespread in lymphocytes, it will also be of benefit to investigate its effect on immune surveillance. We postulate that early LOY in tumor evolution is an adaptive strategy by tumor cells to evade immunity, with deep biological and therapeutical implications …”

Theodorescu said the new findings could also have implications for women, even though they do not have a Y chromosome. The Y chromosome contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.

“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,” Theodorescu said. “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.”

More speculatively, the team further suggested, “… transient pharmacologic inhibition of UTY and KDM5D may offer enhanced therapeutic benefits for patients with Yhigh tumors who are undergoing ICB therapy. Future studies will be required to understand the mechanism of LOY-driven tumor evasion and to specifically define the molecular circuitry that connects the loss of UTY and/or KDM5D to CD8+ T-cell exhaustion in the TME.”

Preliminary data not yet published in addition indicates that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu noted. “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 Shlomo Melmed, MB, ChB, 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.”

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