Debasish SundiOngoing research conducted by physician-scientists from The Ohio State University Wexner Medical Center has revealed promising insights about the tumor immune microenvironment in bladder cancer and may help explain why 75-80% of new bladder cancers occur in males.

In addition to finding that urine-derived lymphocytes (UDLs) may serve as an indicator of tumor-infiltrating lymphocytes (TILs), the researchers showed males with bladder cancer had much higher rates of T-cell dysfunction than females with bladder cancer – a disparity that suggests androgens may affect anti-tumor immunity in bladder cancer.

To further validate their findings, the team has partnered with researchers from other medical institutions. Together, their efforts may lead to new, more personalized treatment strategies for bladder cancer.

A novel, noninvasive approach to mapping the tumor immune infiltrate

Urologic oncologist Debasish Sundi, MD, is a bladder cancer surgeon and researcher at the Ohio State Wexner Medical Center. When he began studying UDLs several years ago, his goal was to find a noninvasive way to profile bladder cancer immune cells.

“The composition of TILs, or the immune cells that infiltrate a tumor, may help us predict which therapies will be most effective for each patient,” Dr. Sundi says. “But analyzing bladder cancer TILs requires surgery to obtain tumor tissues, which is invasive and comes with risks. And once we remove the tumor or bladder, we’ve already administered surgical therapy, sometimes making the question of medical therapy a moot point.”

Using spectral flow cytometry, Dr. Sundi and his team analyzed biospecimens from patients with bladder cancer who enrolled in Ohio State’s bladder cancer registry. They found that UDLs provided a relatively robust picture of TILs, particularly of tumor-infiltrating T cells.

“This was an exciting finding, which we’re now studying on a larger scale in the context of prospective, well-controlled clinical trials,” Dr. Sundi says.

His lab has collaborated with scientists from Penn State Cancer Institute on a phase II clinical trial studying the use of a checkpoint inhibitor with radiation therapy in certain patients with urothelial cancer. And they’ve partnered with researchers from Memorial Sloan Kettering Cancer Center on a prospective study evaluating the use of Bacillus Calmette-Guérin immunotherapy plus gemcitabine in people with recurrent, non-muscle invasive bladder cancer.

“In addition to validating whether UDLs serve as a biomarker for TILs, we’ve refined our analyses to see whether UDLs reflect a tumor’s response to these different therapies,” Dr. Sundi says.

A strong, biologic explanation for the male sex bias in bladder cancer

As part of their pilot work with UDLs and TILs, the research team also compared T cells in men and women with bladder cancer. They discovered the T cells in males are often exhausted or nonfunctional, while those in females are usually activated and functional.

“We established a link between male T-cell dysfunction and androgens in both molecular studies and animal models,” Dr. Sundi says. “For example, we analyzed T cells in mouse models of bladder cancer and found a skew toward an exhausted state in male T cells. This state was dependent on androgen signaling on T cells.”

Dr. Sundi is now pursuing a more in-depth study of the androgen receptor and its impact on the anti-tumor response in males. He’s the site principal investigator of a new, National Cancer Institute-funded trial that will study antiandrogen medical therapy in the context of bladder cancer prevention.

Dr. Sundi’s lab will help manage the immuno-oncology correlative work for this multicenter trial.

“We’ll study UDLs from the participants’ urine specimens before and after treatment,” he says. “This will help us understand if – and how – antiandrogen therapy changed the tumor immune microenvironment.

Ultimately, this may be important early work in establishing immunotherapy-based strategies for primary or secondary bladder cancer prevention.”

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