If the Y chromosome is lost in men’s blood and cancer cells, you have an increased risk of dying from cancer. Doctors have now found out why this is. Accordingly, the loss of the male sex chromosome also affects other cells in the tissue around the tumor. This has a negative effect on the function of the immune system, which means that more aggressive types of cancer can develop, as the team reports in “Nature”. The findings could now help to optimize immunotherapy and thus increase the chances of survival of men with cancer.
Each cell in the body of men usually contains an X and Y chromosome. But in the course of life the white blood cells often lose their y chromosome. This “y loss” in the genome is not hereditary, but probably an aging phenomenon or consequence of the lifestyle and occurs frequently in older men. The disappearance of the Y chromosome can damage the heart, brain and other organs and thus shorten the lifespan of men. When men also develop a tumor, doctors always observe that these people die more often from cancer than men, in whose blood cells the y chromosome is still present.
Even non-cancer cells lose their y chromosome
Researchers from the Cedars-Sinai Medical Center in Los Angeles have now examined why this is the case. In previous studies, they had already found that the tumor cells also lose their y chromosome in bladder cancer. Now the doctors have evaluated existing genome data sets of around 4,000 people to find out whether this is the case with other types of cancer and how the Y loss affects it. They indirectly closed from the active genes whether a Y chromosome was present or not. In addition, they also examined tissue samples from tumor patients and mice with Y loss in all body cells.
It was shown that in all 29 types of cancer not only the white blood cells lose their y chromosome, but also the cancer cells in the tumor. Surprisingly, the team also discovered that normal cells in the tissue in and around the tumor, including epithelial cells, connective tissue cells and immune cells, no longer have a y chromosome. “This result was unexpected because immune cells are much more stable than cancer cells,” Nicholas McGranahan from University College London and Rahul Roychoudhuri from the University of Cambridge write in a comment on the study. The T cells of the immune system, which actually attack and combat the cancer cells, were also affected by loss of chromosome. Without a Y-chromosome, the immune cells could no longer do this task so effectively and more aggressive types of cancer developed, as the team stated.
“If cancer cells no longer have a y-chromosome, it is very likely that immune cells have also lost their y chromosome. The simultaneous y loss in these two cell types correlated with hyperaggressive cancer cells and incorrect immune cells that are supposed to attack the cancer cells. Medical Center. Chen and colleagues conclude that the tumors can escape through their y loss of immune recognition and suppression, therefore become more aggressive and therefore affected patients die more frequently from cancer. How exactly and in what order the different cell types in the tumor environment lose their y chromosome and whether they influence the Y loss of loss is not evident from the data and must be further researched.
Adjustments in immunotherapy necessary?
Thanks to the findings, however, cancer patients could hope for better therapy in the future: “The study has potential effects on current immunotherapies, including car-t therapy,” says senior author Dan Theodorescu from the University of Arizona in Tucson. Because this cancer therapy relies on the body’s own T cells to combat cancer. The defense cells are removed from the body, optimized in the laboratory and then returned to the patient. “We suspect that therapies with T cells to which the Y chromosome lack, are significantly less effective than those with an intact y chromosome,” says Knott.
Follow studies now have to clarify whether the Car-T cell therapy can be adjusted so that it also works for men with Y loss. “Perhaps the T cells from a patient’s immune system could be examined for a possible Y loss before they are used in the treatment,” said Theodorescu. This could then increase the survival rate of men with cancer.
Source: Xingyu Chen (Cedars-Sinai Medical Center, Los Angeles) et al.; Nature, DOI: 10.1038/S41586-025-09071-2
