Study shows loss of Y in blood cells hinders immune response to cancer

A study initiated by a University of Arizona Comprehensive Cancer Center physician-scientist defined for the first time how loss of the Y chromosome in male immune cells negatively affects immune system function, which may explain why loss of Y is associated with lower cancer survival rates. The paper “Concurrent loss of the Y chromosome in cancer and T cells impacts outcome,” was published today in Nature.

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In males, each cell in the body usually contains one X and one Y chromosome. “Loss of Y” is a common, nonhereditary genetic change in men in which an immune cell in the blood loses its Y chromosome. It is often associated with aging. Loss of Y has been linked to increased mortality from carcinomas for many years, though no one knew why.

This study is the first to identify and define the relationship between loss of Y in white blood cells, immune cells and tumors, providing insights as to why men with loss of Y have increased cancer risks and poorer outcomes.

“These findings represent a big step forward in our understanding of why men with loss of Y in their blood cells have a higher mortality from cancer. It turns out it’s because these cells make the immune system infiltrating the cancer less effective,” said Dan Theodorescu, MD, PhD, the Nancy C. and Craig M. Berge endowed chair for the director of the Cancer Center and a professor in the College of Medicine – Tucson. 

“We hope this provides a solid lead and framework for the nascent Y chromosome field to pursue so we can collectively better understand all the possible biological implications of this finding and how to use them to develop more effective approaches in prevention, treatment resulting in higher survival rates for patients.”

The research team discovered that loss of the Y chromosome – previously identified in malignant epithelial cells by the Theodorescu lab – also occurred in nearby noncancerous tissues, including connective tissue and immune cells.

Most notably, the team found that this chromosomal loss in helper and cytotoxic T cells, which are responsible for attacking cancer cells, was associated with a reduced ability to kill those cancerous cells. The findings suggest a mechanism by which tumors may evade immune detection and suppression.

Finally, the research team found that loss of Y in epithelial cells, combined with loss of Y in T cells, resulted in more aggressive cancers and lower survival rates in patients.

“The study has potential implications for current immunotherapies, including CAR T therapy,” Theodorescu said. “Further research is clearly needed but perhaps immunotherapies using cells from a patient’s immune system could be screened for loss of Y before being used in treatment.”

The idea for this investigation originated with Theodorescu, then at Cedars-Sinai Medical Center, who was intrigued by a potential link he had observed in his earlier research. He reached out to his longtime collaborator Simon Knott, PhD, to explore the idea further in this study.

The study was funded in part by the National Cancer Institute, a division of the National Institutes of Health, under award no. CA278732 to Theodorescu.