ECANCER
As men age, some of their cells lose the very thing that makes them biological males – the Y chromosome – and this loss hampers the body’s ability to fight cancer, according to new research from Cedars-Sinai Cancer.
The study, published in the leading scientific journal Nature, found that loss of the Y chromosome helps cancer cells evade the body’s immune system.
This common impact of the aging process in men results in aggressive bladder cancer, but somehow also renders the disease more vulnerable – and responsive – to a standard treatment called immune checkpoint inhibitors.
Based on their research, investigators are developing a test for loss of the Y chromosome in tumors with the goal of 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.”
Lead collaborators on the study also included Johanna Schafer, a postdoctoral fellow, and Zihai Li, MD, PhD, medical oncologist and immunologist, 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; men have one X and one Y chromosome, while women have two X chromosomes. In men, loss of the Y chromosome has been observed in several cancer types, including 10%-40% of bladder cancers.
Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease.
The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.
The investigators then reviewed data on two groups of men. One group had muscle invasive bladder cancer 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.
They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.
To determine why this happens, investigators next compared growth rates of bladder cancer cells from laboratory mice.
The investigators grew cancer cells in a dish where the cells were not exposed to immune cells.
