This may be the reason men becoming more vulnerable to certain cancers

In the majority of males, each cell typically contains one X chromosome and one Y chromosome. Nevertheless, it has been observed that as men age, there is a tendency for some of them to lose the Y chromosome in certain cells. A recent study involving mice hints that this phenomenon could weaken their defenses against specific types of cancer.

According to the research, which was released on June 21 in the scientific journal Nature, the absence of the Y chromosome in some cells of males might inadvertently provide an opening for cancer to evade the immune system, particularly in cases of bladder cancer. This in turn may facilitate the cancer’s growth and spread at an accelerated pace.

“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” remarks corresponding author Dr. Dan Theodorescu. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

There might be a glimmer of hope emerging from these findings: The very mechanisms that cause the cells of bladder cancer in men who have lost the Y chromosome to be more virulent might also render them more susceptible to a class of cancer treatments known as immune checkpoint inhibitors.

It has been established in the past that the loss of the Y chromosome is linked with a heightened risk of various health issues, such as heart disease and Alzheimer’s disease. This loss can be noticed in diverse cell types, encompassing blood cells and also varying cancer cells. The study’s authors noted that this includes an estimated 10% to 40% of bladder cancers, which predominantly affect men.

To evaluate the repercussions of this phenomenon on bladder cancer, the researchers measured the growth rates of bladder cancer cells in two batches of lab mice – one batch received injections with Y-negative cells, while the other with Y-positive cells. The tumor cells without the Y chromosomes grew alarmingly fast, at double the rate compared to those with the chromosomes.

In an attempt to understand the reason behind this, the researchers repeated the experiment, but this time using immunocompromised mice. In this case, the tumors grew at a comparable pace regardless of the presence of the Y chromosome, hinting at the involvement of the immune system.

The experiment was conducted again using genetically modified mice lacking different kinds of immune cells. The study found that T-cells, which are instrumental in combating cancer cells, were most influenced by the loss of the Y chromosome.

The study suggests that Y-negative cells may be inducing a state known as T-cell exhaustion, which is characterized by the immune cells’ diminishing capacity to eliminate certain cells, such as cancer cells. Consequently, cancer cells can slip past the immune defense, leading to a more vigorous growth of tumors than would occur with functional T-cells.

In such instances, medical practitioners could possibly enhance a patient’s immune defense by employing immune checkpoint inhibitors. These drugs reinvigorate T-cells to the extent that they resume attacking cancer cells. The study revealed that mice with Y-negative tumors responded more favorably to this treatment compared to those with Y-positive tumors.

To investigate the implications on human cancer therapy, the researchers analyzed data from two sets of men with bladder cancer, and they were able to infer Y chromosome loss in tumor cells. The first set included patients who underwent bladder removal, while the second set consisted of those treated with immune checkpoint inhibitors.

Among the first set, patients with Y chromosome loss in their tumors had lower survival rates compared to those with intact Y chromosomes. However, among those treated with immune checkpoint inhibitors, patients with Y chromosome loss exhibited a more favorable overall outlook compared to those with intact Y chromosomes.

The study indicates that Y chromosome loss might partly explain the increased incidence of bladder cancer as men get older.

However, it’s important to note that the loss of the Y chromosome may not affect all cancers in the same manner, and this has led to debates regarding its universal impact on patient prognosis. For instance, another recent study in Nature revealed that in colorectal cancer in mice, Y chromosome loss might actually make the tumors less aggressive.

Regardless of the type of cancer, an essential subsequent step should be to devise a clinical test capable of determining Y chromosome loss in tumors, enabling physicians to customize treatments accordingly.

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