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Thomas Flaig, MD

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Do Male Sex Hormones Play a Role in the Higher Rates of Bladder Cancer in Men?

By: Victoria Kuhr, BA
Posted: Friday, July 29, 2022

Xue Li, PhD, of Cedars-Sinai, Los Angeles, and colleagues observed that a sex-specific regulon in progenitor-exhausted CD8-positive T cells may play a role in the development of bladder cancer. CD8-positive T-cell exhaustion appears to be caused by androgen receptors increasing the gene expression of Tcf7/TCF1, which tends to result in more aggressive bladder cancer in males than females. In addition, they found that ablation of the androgen-AR axis may “rewire” the tumor microenvironment and thereby potentiate the efficacy of anti–PD-1 immune checkpoint blockade. These findings were published in Science Immunology.

“We observed that biology of sex, not just behavior, is an important factor in cancer development,” said Dr. Li in a Cedars-Sinai press release. “These findings suggest male patients may benefit more from immunotherapy when combined with androgen-deprivation therapy.”

The study used mouse models diseased with bladder cancer to show tumor aggressiveness between males and females. More aggressive tumors were found in male mice, which mimicked the predicted incidence bias occurring in humans. The study authors used this bias to determine whether androgen receptors acting on CD8-positive T cells may be part of the biologic reason males have an increased incidence of bladder cancer and worse clinical outcomes compared with females.

Based on cancer epidemiology statistics, males are three to five times more likely than females to develop bladder cancer. Sex hormones (androgens) are produced in higher amounts in males. By means of the mouse model, androgens were observed to interfere with how the immune system responds to pathogens. Androgens appear to block the activity of CD8-positive T cells. The genetic sequencing of CD8-positive T cells from the tumors in males showed more signs of exhaustion and dysfunction as a result of androgen activity. According to the investigators, androgen-deprivation therapy was found to be effective in reducing the size of bladder tumors in male mice and improved the efficacy of immunotherapy.

Disclosure: For full disclosures of the study authors, visit www.science.org.


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