Y chromosome loss linked to poor cancer outcomes

When cancer cells in male patients and immune cells in their tumors both lose the Y chromosome, those patients tend to experience poorer outcomes than patients without Y chromosome loss, according to new findings from Cedars-Sinai investigators. Their work, published in the scientific journal Nature, could lead to ways to make some cancer treatments more effective.

The Y chromosome is one of two chromosomes that determine biological sex in mammals. Females have two X chromosomes, males have one X and one Y chromosome, and it is common for males to lose the Y chromosome in some of their cells as they age.

Cedars-Sinai research published in 2023 found that loss of the Y chromosome in bladder cancer cells in men helped those cells evade the body's immune system, allowing the cancer to grow. However, tumors with loss of the Y chromosome also were more susceptible than those with an intact Y chromosome to immune checkpoint therapy.

Given the previous findings, that Y chromosome loss in cancer cells was problematic in most male tumors, study co-senior authors Simon Knott, PhD, assistant professor of Biomedical Sciences at Cedars-Sinai, and Dan Theodorescu, MD, PhD, wanted to investigate the consequences of Y chromosome loss in males with other types of cancer, Knott said. 

Using large publicly available datasets, the new study examined loss of the Y chromosome in cancer cells from a range of cancers. Unexpectedly, the investigators found that many other cell types associated with tumors also had Y chromosome loss, prompting further investigations, Knott said.

When we started to investigate Y loss in other cells in the tumor, our jaws dropped because the link between loss of the Y chromosome in cancer cells and in immune cells from the same tumor was so striking. Our work showed that if cancer cells lost the Y chromosome, it was very likely immune cells would also have lost the Y chromosome. Losing the Y chromosome in both these cell types at once correlated with hyperaggressive cancer cells and malfunctioning immune cells that are meant to attack the cancer cells. This creates an aggressive tumor with very poor outcomes."

Simon Knott, PhD, Assistant Professor of Biomedical Sciences, Cedars-Sinai

In addition to the cancer databases, investigators confirmed their findings by looking at loss of Y in patient tumor samples and in preclinical studies using additional techniques to measure Y chromosome loss, which confirmed their findings.

The findings could also have implications for patients receiving T-cell therapies, where immune cells called T-cells are harvested from a patient, altered in the lab so that they are more effective in fighting cancer, then delivered back to the patient.

"Our findings suggest that screening for loss of the Y chromosome in those T-cells or any product generated from them before being given back to a patient could be extremely important," Knott said. "We predict that cellular therapies with T-cells lacking the Y chromosome will be significantly less effective than those with an intact Y chromosome."

Further research is needed to help investigators understand how best to adapt these therapies to account for loss of Y.

"Given that a high percentage of older, healthy men experience loss of the Y chromosome in at least some of their cells, these findings could affect many cancer patients," said Robert Figlin, MD, interim director of Cedars-Sinai Cancer and professor of Medicine and Biomedical Sciences. "Continued investigation into how to translate these findings to more effective therapies fits well with our focus on precision medicine as a way to improve patient outcomes."