Researchers have found that the loss of the Y chromosome, a common impact of the aging process in men, may help cancer cells evade the body’s immune system and result in aggressive bladder cancer—but it may also render the disease more vulnerable and responsive to immune checkpoint inhibitors—according to a recent study published by Abdel-Hafiz et al in Nature.
Background
In humans, each cell normally has one pair of sex chromosomes: men have one X and one Y chromosome, whereas women have two X chromosomes. However, as men age, some of their cells lose the Y chromosome—potentially hampering the body’s ability to fight cancer. Loss of the Y chromosome has been observed in cardiovascular disease, Alzheimer’s disease, and 10% to 40% of bladder cancers.
Immune checkpoint inhibitors, one of the two mainstays of bladder cancer treatments currently available, are capable of reversing T-cell exhaustion to aid the body’s immune system in fighting 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,” explained senior study author Dan Theodorescu, MD, PhD, Professor of Surgery as well as Pathology and Laboratory Medicine and Director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai. "We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively,” he stressed.
Although female patients do not have a Y chromosome, the new findings could have implications for them as well. The Y chromosome contains a set of related genes—called paralogue genes—on the X chromosome that might play a role in both women and men.
"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,” Dr. Theodorescu suggested. "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,” he detailed.
Study Methods and Results
The Y chromosome contains the blueprints for certain genes. After analyzing the way these genes were expressed in normal cells in the bladder lining, the researchers developed a scoring system to measure the loss of the Y chromosome in tumors with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.
The researchers then examined the data of two patient groups: male patients with muscle-invasive bladder cancer who had undergone cystectomy but were not treated with immune checkpoint inhibitors and patients who had participated in a clinical trial and were treated with immune checkpoint inhibitors. They found that patients with loss of the Y chromosome had poorer prognoses in the first group and much better overall survival rates in the second group.
To determine why this occurred, the researchers next compared the growth rates of bladder cancer cells using laboratory mice. They grew the bladder cancer cells both in a dish where the cells were not exposed to immune cells and in mice that were missing T cells. In both cases, the tumors with and without the Y chromosome grew at the same rate. In mice with intact immune systems, the tumors lacking the Y chromosome grew at a much faster rate than those with the intact 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,” Dr. Theodorescu emphasized. "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,” he added.
Based on their findings, Dr. Theodorescu and his colleagues also inferred that tumors missing the Y chromosome, although more aggressive, could also be more vulnerable and responsive to immune checkpoint inhibitors. "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,” highlighted lead study author Hany Abdel-Hafiz, PhD, MS, Research Associate Professor of Medicine at Cedars-Sinai.
Preliminary data, not yet published, also demonstrated that the loss of the Y chromosome may also render prostate cancers more aggressive.
"Our [researchers] postulate that [the] loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs,” detailed Shlomo Melmed, MB, ChB, FRCP, MACP, Distinguished Professor of Medicine, the Helene A. and Philip E. Hixon Distinguished Chair of Investigative Medicine, Executive Vice President of Academic Affairs, and Dean of the Medical Faculty at Cedars-Sinai, who was not involved in the study. "This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward,” he underscored.
Disclosure: The research in this study was supported in part by grants from the National Institutes of Health; The Ohio State University Comprehensive Cancer Center Tumor Immunology T32 postdoctoral fellowship award; and the Immune Monitoring and Discovery Platform and the Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center. For full disclosures of the study authors, visit nature.com.
