Men with lung adenocarcinoma, the most common form of lung cancer, often lose the Y chromosome in their tumor cells, which helps tumors evade the immune system but improves response to a key immunotherapy drug. This phenomenon, studied by researchers in Boston, highlights the complex role of Y chromosome loss in cancer progression. While it may worsen tumor growth, it does not appear to affect overall survival in this cancer type.
As men age, many cells lose their Y chromosomes, a mutation linked to heart disease and reduced lifespan. In cancer, this loss has been studied most in bladder tumors, but new research focuses on lung adenocarcinoma, which originates in the mucus-making cells lining the airways.
Dawn DeMeo at Brigham and Women’s Hospital in Boston and her colleagues, including John Quackenbush at Harvard University, analyzed Y chromosome gene expression in a public database of lung adenocarcinoma samples. They found that cancerous cells frequently lacked Y chromosomes, unlike healthy lung cells or immune cells, and this occurred regardless of smoking history—a known risk factor for both lung cancer and Y loss.
The loss accumulates over time, with some patients showing a greater proportion of tumor cells without Y. This is tied to reduced expression of antigens that normally alert T-cells to attack abnormal cells. “As the tumour cells lose their Y chromosomes, they’re increasingly able to evade immune surveillance, and that would argue that they’re selected for,” says Quackenbush. Indeed, T-cells were less common in Y-loss tumors.
However, this same loss correlates with better outcomes from pembrolizumab, an immune checkpoint inhibitor that boosts T-cell activity against tumors. In data from 832 patients treated with the drug, Y loss was associated with improved responses. “When you have LOY [loss of Y], you’re more responsive to checkpoint inhibitors,” says Dan Theodorescu at the University of Arizona, who observed similar effects in bladder cancer.
Despite Y loss shortening men's lifespans generally, it does not impact survival in lung adenocarcinoma. Theodorescu suggests further research could position Y loss as a biomarker for treatment decisions, varying by cancer type.