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Team Tracks Immune T Cell Consequences of Y Chromosome Loss, Bladder Cancer Consequences

A functional immune system capable of staving off cancer cells appears to rely on the presence of Y sex chromosomes in biological males, according to new research by a Cedars-Sinai Medical Center-led team reporting in Nature, while aging-related Y chromosome loss appears to bump up the risk of developing aggressive forms of bladder cancer. With the help of a Y chromosome-encoded gene expression-based score for loss of the chromosome, the researchers found that higher-than-usual rates of Y chromosome loss tended to coincide with more aggressive disease and poorer survival outcomes in 300 locally advanced, muscle invasive bladder cancer cases included in the Cancer Genome Atlas project, though follow-up analyses suggest that Y chromosome loss is also linked to improved response to checkpoint inhibitor immunotherapy. With a series of flow cytometry, single-nucleus RNA sequencing, spatial proteomic, and other experiments in cancer cell lines and mouse models of disease, they teased out ties between Y chromosome loss and the function of CD8-positive immune T cells in the tumor microenvironment. "Together, these results demonstrate that cancer cells with [loss of the Y chromosome] mutations alter T cell function, promoting T cell exhaustion, and sensitizing them to PD-1-targeted immunotherapy," the authors report. In a related Nature study, a University of Texas MD Anderson Cancer Center team considers sex-related differences in colorectal cancer, focusing on the consequences of increased expression of a histone demethylase gene found on the Y chromosome.