COLUMBUS, Ohio -- A new study published in the journal Nature shows that loss of the Y chromosome in males with bladder cancer correlates with poor prognosis but also makes tumors more susceptible to immunotherapy. Researchers with the Pelotonia Institute for Immuno-Oncology (PIIO) at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) were lead collaborators in the study, which was co-supervised by Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer Center (CSCC) in Los Angeles, and Zihai Li, MD, PhD, director of the PIIO at the OSUCCC – James. There are two sex chromosomes in humans: X and Y. The Y chromosome is only present in males. As men age, loss of the Y sex chromosome (LOY) occurs in many organs and cells. Many cancers also display LOY, including 10-40% of bladder cancers, but its clinical and biological significance is unknown. The research team – including co-first authors Johanna Schafer, PhD (a former postdoctoral scholar in Dr. Li’s lab; now with Roche Diagnostics Solutions in Arizona), Hany Abdel-Hafiz, PhD, and Xingyu Chen, (both of CSCC) – evaluated differences in tumors that retain or lose the Y chromosome (Y-positive vs. Y-negative), either through natural occurrence or targeted deletion. They found that Y-negative tumors are more aggressive than Y-positive tumors in hosts with a normal immune system. “This is the first study to make a connection between LOY and the immune system’s response to cancer, explaining that loss of the Y chromosome allows bladder cancer cells to evade the immune system and grow more aggressively,” said Dr. Li. Using techniques to measure RNA and protein levels in human bladder cancers, the team found that Y-negative tumors strikingly disable so-called “cancer killer” CD8+ T cells, a population of immune cells that are critical for mounting an antitumor response. Dr. Li coined this phenomenon ‘LOYalT,’ for “LOY cancer alters T cell function” (see illustration). Of note, he adds, “compared with Y-positive tumors, Y-negative tumors are more responsive to anti-PD-1 immune checkpoint blockade in both mouse models and patients with cancer.” (PD-1 expression on T cells prevents them from acting as “cancer killers.” Immune checkpoint blockade therapy often blocks PD-1, boosts T cell function, and is commonly used to treat cancers.) “Together, these results demonstrate that cancer cells with LOY mutations induce T cell dysfunction, but these T cells can be re-energized to eliminate the tumor using PD-1-targeted immunotherapy,” said Li. “This work provides insights into the basic biology of LOY mutation and suggests ‘LOYalT’ is a potential biomarker for improving cancer immunotherapy.” This study was made possible through collaborations established by the PIIO, a comprehensive bench-to-bedside research initiative focused on harnessing the body’s immune system to fight cancer at all levels, from prevention to treatment and survivorship. Li is the founding director of the PIIO, which was established in 2019 through a pledge of $102 million from the OSUCCC – James and Pelotonia, an annual cycling event that has raised more than $258 million for cancer research at Ohio State. Other study authors in the Nature article include Tong Xiao, MS (a PhD student), and Timothy Gauntner, DO, PhD (a medical oncology fellow), both from the PIIO at the OSUCCC – James. The work was supported in part by multiple grants from the National Institutes of Health (NIH), including a recent $11.3 million collaborative Program Project Grant awarded by the National Cancer Institute (P01 CA278732) to Cedars-Sinai and Ohio State, with Xue Sean Li, PhD of CSCC as the principal investigator. ### MEDIA CONTACT: Amanda Harper OSUCCC – James Media Relations Amanda.Harper2@osumc.edu | 614-685-5420 *Figure shows a visual abstract of 'LOYaIT' to visualize the concept that loss of Y chromosome in cancer contributes to immune evasion. Illustration by Jared Schafer for the PIIO. *News release written by Bob Hecker