The Y chromosome in men is not only important for reproduction: Evidence is mounting that this genetically impoverished, small sex chromosome also plays an important role in health. This also applies to cancer tumors, as a study has now shown. The researchers investigated the consequences of losing the Y chromosomes in cancer cells, as is the case in 10 to 40 percent of tumors in bladder cancer. It was found that such Y-negative tumors in mice grew twice as fast as tumors with intact Y chromosomes. The reason for this is apparently premature exhaustion and inhibition of T cells in the immune system, which then can no longer effectively fight the cancer cells. On the other hand, there is hope that these Y-poor cancer tumors react particularly sensitively to immunotherapy.
While the biological female gender is characterized by two X chromosomes, men have a Y chromosome instead of the second X chromosome. However, this has lost almost 90 percent of its original gene set in the course of evolution and is therefore only a third as large as its female counterpart. The few genes that are still on the Y chromosome mainly regulate sperm production and sex development, the rest is filled with highly variable gene sections with largely unknown functions. From this, some scientists even concluded that the Y chromosome is not essential and could even disappear completely one day. At first glance, this is supported by a chromosomal aging phenomenon in many men: In around 40 percent of all 70-year-old men, some of the blood and body cells have lost their Y chromosome - apparently without serious consequences. But in 2022 it was found that men with an increased loss of the Y chromosome (LOY) have a greater risk of cardiovascular disease, Alzheimer's disease and other age-related diseases.
Cancer tumors without a Y chromosome
A team led by Hany Abdel-Hafiz from the Cedars-Sinai Medical Center in Los Angeles has now investigated the consequences of the loss of the Y chromosome for cancer. "Such a loss has already been observed in several types of cancer, including 10 to 40 percent of bladder cancer cases," the scientists explain. "However, the clinical and biological significance of this phenomenon is unknown." To find out more, they first developed a method that allowed them to determine the degree of Y chromosome loss in tissue samples from more than 1,100 male bladder cancer patients. To do this, they compared the activity of 18 genes of the Y chromosome, which can be seen in the RNA, with reference values of healthy, intact cells. They then examined whether and how the course of the cancer and survival differed in patients with comparable therapies and cancer stages with and without Y chromosome loss.
The analysis revealed that patients with low Y content in their bladder tumor developed a lower chance of survival and a poorer prognosis. Additional analyzes based on genetic data showed the same for twelve other types of cancer. In order to find out which biological mechanisms are behind this, Abdel-Hafiz and his team carried out experiments with mice. To do this, they first cultivated bladder cancer cell lines and removed the Y chromosomes from some of the cancer cells using Crispr/Cas gene scissors. They then injected these Y-positive and Y-negative cancer cells into mice in order to be able to observe the growth of the tumors. The result: "We found that the Y-negative tumors had a growth rate that was around twice as high as the Y-positive tumors," the researchers report. However, when they repeated this experiment with mice without a functioning immune system, these differences did not exist: cancerous tumors with and without a Y chromosome grew at the same rate. "The fact that we only saw the differential growth rate when the immune system was involved was an important key," explains senior author Dan Theodorescu of Cedars-Sinai Medical Center.
Impaired T cells
Further analysis revealed that the more rapid growth of tumors without a Y chromosome is closely linked to their effect on the T cells of the immune system. Normally, these cells have the ability to recognize and specifically attack cells that have undergone pathological changes. But while T cells were plentiful in the Y-negative tumors from the mice, most of them were dormant and unable to kill the cancer cells. "Our data support the notion that the loss of Y chromosomes alters the tumor microenvironment and prematurely depletes CD8+ T cells," the team reports. "This is the first time that such a link between the loss of the Y chromosome and the immune system's response to cancer has been demonstrated." The researchers suspect that the loss of the Y chromosome in cancer cells evolved as an adaptation. Eliminating the chromosome makes it easier for them to evade attacks by the immune system. How and why the cancer cells affect the T cells has not yet been clarified.
However, the new findings also hold hope for those affected, because another experiment showed that the Y-negative cancer cells can disable the T cells - but this effect can be reversed by an immunotherapy that has already been tested against some types of cancer. Special antibodies are administered that dock to inhibiting receptors on the surface of the T cells. As a result, these so-called checkpoint inhibitors release the brakes on the immune cells and make them active again. In the study, this therapy worked significantly better in mice with Y-negative tumors than in mice with intact Y chromosomes in their cancer cells. The scientists were able to find something similar in bladder cancer patients who had been treated with checkpoint inhibitors as part of a clinical study. In her opinion, this opens up new perspectives for the targeted fight against aggressive, fast-growing cancer tumors.
Source: Hany Abdel-Hafiz (Cedars-Sinai Medical Center, Los Angeles) et al., doi: 10.1038/s41586-023-06234-x