Loss of the Y chromosome, a common feature of male aging, may allow bladder cancer to evade the immune system while simultaneously making tumors more susceptible to immunotherapy.
The results, published in the journal Nature, say our biological sex is determined by a pair of chromosomes, X and Y, typically present in human cells. While females usually have two X chromosomes, men typically have one X and one Y.
However, when male cells mature, they may gradually lose their Y chromosomes. This has been associated with several cancer types, including Alzheimer's and cardiovascular diseases. About 10 to 40% of bladder tumors have Y chromosome deletion. However, it is unclear how this might affect patients. A previous study by the University of Virginia School of Medicine also revealed that loss of the Y chromosome can lead to premature death.
As a result, Cedars-Sinai Medical Center researchers looked at how Y chromosome deletion may connect to the biology and therapy of these tumors using information from patients and lab models.
First, based on the expression of Y chromosome genes, the researchers developed a scoring system for bladder malignancies that assesses Y chromosome deletion in the cells that line the bladder.
These results were compared using information from two groups of men: one group with advanced bladder cancer who underwent bladder removal but did not receive immunotherapy, and the other group with advanced bladder cancer who received an immune checkpoint inhibitor as part of a clinical trial.
In the first group of patients with Y chromosomal deletion, the prognosis was worse, while in the second group, the overall survival rates were significantly higher. The researchers used laboratory mice to investigate why this was taking place. Tumor growth was comparable in animals without T cells, which were used to produce bladder cancer cells with and without Y chromosome deletion.
However, tumors without the Y chromosome developed considerably more rapidly when produced in mice with T cells.
"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," says the senior author of the study Dan Theodorescu.
"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."
The researchers conclude that while developing more aggressively, these tumors were more susceptible to immune checkpoint inhibitors based on evidence from the mice and human investigations. One of the two essential therapies for bladder cancer now in use, these medications assist in reversing T-cell fatigue and redirecting the battle to the cancer cells.
Shlomo Melmed from Cedars-Sinai concludes: "Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs."
"This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward."
- Nature. Y chromosome loss in cancer drives growth by evasion of adaptive immunity
- National Institute of Health. A Study of Atezolizumab in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer (Cohort 2)
- Science. Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality