Y chromosome loss may be key to unlocking more effective bladder cancer treatment for men
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Key takeaways:
- Y chromosome loss helps bladder cancer tumors evade the body’s immune system response.
- Y chromosome loss may make bladder cancer tumors more responsive to treatment with immune checkpoint inhibitors.
A series of studies showed that loss of the Y chromosome helps cancer evade the body’s immune system response, resulting in more aggressive bladder cancer in men as they age.
The findings, published in Nature, revealed that although Y chromosome loss diminishes immune response to fighting cancer in older men, the process may make bladder cancer more susceptible to treatment with immune checkpoint inhibitors.
The investigators hope the research will lead to a validated Y chromosome loss biomarker test for men that can help guide use of more effective treatment for bladder cancer.
“These results are a reminder that we need to be mindful of biological sex differences when we do research,” Dan Theodorescu, MD, PhD, director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, told Healio. “If the biomarker works, then it will likely help almost anyone receiving immunotherapy around the world.”
Background
Bladder cancer is a sexually dimorphic disease, meaning there are systematic differences in the way the disease presents itself depending on the individual’s sex biology, according to Theodorescu.
For example, bladder cancer affects men more often even after adjusting for risk factors, whereas women tend to have more aggressive forms of the disease, he said.
“It’s either hormones or chromosomes,” Theodorescu told Healio, referring to why bladder cancer affects men and women differently.
“One of the things that's striking about the chromosomes — and one of the reasons why we started deep getting more deeply involved in this area — is that the Y chromosome not only loses expression in bladder cancer, but it tends to be lost among a proportion of men who don't have cancer as they age,” he added.
This loss of Y chromosome expression coincides with a known loss of white blood cells, which puts men at increased risk for heart disease, neurologic disease and cancer, Theodorescu said.
“That coupled with the fact that bladder cancer is a sexually dimorphic disease got me thinking that the two things that could be driving increased bladder cancer risk are related to chromosomes or hormones, so we decided to delve into the chromosomes,” he said.
Methodology and findings
Theodorescu and colleagues performed a series of genomic and transcriptomic studies to determine the biologic significance of Y chromosome loss in men with bladder cancer.
The investigators started by developing a Y chromosome expression score and applied it to 300 men with locally advanced muscle-invasive bladder cancer (MIBC) using transcriptomic data from The Cancer Genome Atlas. The researchers divided tumor samples from the study cohort into two groups based on low and high expression of the Y chromosome.
They found that men with a low Y chromosome gene expression score had significantly shorter OS than those who had high Y chromosome expression (P = .024).
The researchers then injected male mice with bladder cancer cells containing both low and high expression of the Y chromosome. Results showed that tumors with low expression of the Y chromosome had an approximately twofold higher growth rate compared with high-expression tumors.
Theodorescu and colleagues then injected both bladder cancer cell types into wild-type and immunodeficient male mice and found that tumors with low Y chromosome expression grew significantly faster than high-expression tumors in wild-type mice. However, both cell types grew at the same rate in immunocompromised mice.
“That was the aha moment when we realized that Y-negative tumors are driving their enhanced growth by actually evading the immune system,” Theodorescu said.
High-dimensional flow cytometric analysis indicated that bladder cancer tumors with lower expression of the Y chromosome exhibited a higher proportion of dysfunctional CD8+ T cells in the tumor microenvironment.
“When we looked at infiltration of immune cells into the tumor, we realized that the T cells were being paralyzed,” Theodorescu continued. “That paralysis — which is called exhaustion — could potentially be reversed by checkpoint inhibitors.”
The investigators tested their hypothesis using spectral flow cytometry, which revealed “the most surprising miracle of all,” Theodorescu said.
“Although the Y chromosome-negative tumors were more aggressive,” he said, “they were also highly responsive to checkpoint inhibitors.”
Clinical implications
The results suggest that a bladder cancer tumors’ own evolutionary defense mechanism is also a potential vulnerability that can be leveraged as a possible treatment target, according to Theodorescu.
“The first step would be to get approval for a validated assay that can evaluate tumor cells for loss of the Y chromosome, but also to evaluate its prognostic utility in a much larger set of patients and across multiple cancer types,” he added.
That work is currently under way, and Theodorescu expects his group to submit another study for publication in the coming months that examines use of the assay in actual tissues rather than retrospectively via a genomic database.
Beyond validating the assay, he said putting the knowledge they have gained through this study to clinical use means understanding other reasons for T-cell exhaustion that are not reversed by checkpoint inhibitors.
“The idea would be not only trying to predict who's going to respond to checkpoint inhibitors — which would be a really big advance — but then to take those patients and give them a new combination therapy that actually could elevate them toward a cure,” he told Healio.
For more information:
Dan Theodorescu, MD, PhD, can be reached at Cedars-Sinai Health System, 8700 Beverly Blvd., NT-Plaza Level 2429C, Los Angeles, CA 90048; email: dan.theodorescu@cshs.org.
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