Key Takeaways: • A study by researchers from The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute sheds light on the search for more personalized treatment options for patients with bladder cancer. • The study was recently published in the Journal for Immunotherapy of Cancer. • Researchers say the study opens the door to understanding why men and women experience bladder cancer differently. COLUMBUS, Ohio – As the incidence of bladder cancer rises with the aging population and extends further into younger age brackets, researchers are working to personalize treatment options to improve upon the “one-size-fits-all” approach. A recent study by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) and published in the Journal for Immunotherapy of Cancer may represent a turning point in this quest. “Despite what we know about tumor immunology and response to different immunotherapies, we still treat every patient with bladder cancer (in a given risk category) quite generically, in that little to nothing is tailored to the biology of a person’s particular tumor or their immune cells,” said urologist and co-corresponding author Debasish Sundi, MD, associate professor of urology and member of the Cancer Biology Program at the OSUCCC – James. “That is a gap we wanted to bridge in our study so we can ultimately offer personalized care.” Developing tailored treatments depends on assessing the tumor microenvironment, with a focus on the T-cell lymphocyte differentiation states. To do this, Sundi and his colleagues built on empirical evidence suggesting that urinary-derived lymphocytes (UDLs) are a potential surrogate for tumor-infiltrating lymphocytes (TILs). Because of the proximity of urine to a bladder tumor, urinary biomarkers (gene and protein products) offer insight into the host and tumor immune microenvironment. “We asked, ‘What if we showed a highly matched phenotype between UDLs and TILs, giving us a non-invasive way of understanding the TIL composition among patients who have been diagnosed with bladder cancer?’” said Sundi. Similar phenotypes found The team looked at function and exhaustion of CD4+ and CD8+ T-cell subsets of both UDLs and TILs in 21 patients (including 20 who were treatment-naïve, or had had no previous therapy) with muscle-invasive and high-grade non-muscle invasive bladder tumors. CD8+ T cells are closely associated with antitumor immunity in bladder cancer, and CD4+ T cells have a lesser but potentially significant association. They found that the UDLs and TILs had strongly similar phenotypic profiles, in both superficial and deep tumor sections. “Previous studies have shown that some of the immune cells match with the TILs, but it wasn’t clear whether the phenotype of CD4+ and CD8+ T cells also reflect what's happening in the tumor,” said No-Joon Song, PhD, assistant professor in medical oncology and co-first author of the study. “So, when we analyzed those cells from the patient, they matched nicely with what's happening within the tumor. With the limited number of patient samples, what we can solidly claim is that the UDL phenotype of the lymphocytes that best characterize tumors resembles what's actually happening in the tumor.” “This emerging opportunity to use UDLs opens avenues of non-invasive biomarker development in clinical settings where bladder cancer TILs are hypothesized to predict clinical response,” said Sundi. The team also discovered that the bladder cancer tumor microenvironment in males was more enriched in exhausted CD4+ and CD8+ T cells, while it was enriched for activated T cells in females. They say this finding provides clinical validation of prior research led by Zihai Li, MD, PhD, deputy director for translational research and founding director of the Pelotonia Institute for Immunology Research (PIIO) at the OSUCCC – James. Bladder cancer models have shown that antitumor immunity can be very different based on sex, which may pertain to the higher risk of bladder cancer in men. Dialing down the burden and risk If UDLs can be reliably used to assess T-cell functional status in the tumors, some patients might be found to have tumors that are predicted to respond completely to medical therapy alone, possibly enabling them to avoid endoscopic tumor surgery under general anesthesia and its attendant risks. Another advantage lies in overcoming spatial heterogeneity in biopsies. Assessing biomarkers with transurethral biopsies of bladder cancers is limited by the fact that tissue samples from different geographic areas might differ from one another. “This study shows that a simple urine sample can mirror the immune landscape of bladder tumors with surprising fidelity,” said Li. Implications for predicting therapeutic response With the potential to non-invasively identify patients who may respond to immunotherapies, the findings might inform patient candidacy criteria for trials of new drugs that are being evaluated in bladder cancer clinical trials at the OSUCCC – James. “The phenotype and function of UDLs will provide insight that may dramatically impact the precision with which we can employ immunotherapies in a personalized manner,” said Sundi. Song noted that, with a larger patient sample and data size in the future, UDLs could be correlated with PD-1 or PD-L1 blockade (immune checkpoint blockers) therapy or predict how the UDLs match with overall survival. “By tapping into urine-derived lymphocytes, we now have a non-invasive window into the tumor microenvironment that could help us tailor immunotherapies more precisely,” said Li. “It opens the door to real-time monitoring of treatment response and to understanding why men and women experience bladder cancer differently. The next step is prospective clinical validation, and I’m optimistic that with focused effort, this approach could begin informing patient care within a few years.” This work was made possible by the patients with bladder cancer who volunteered for The Ohio State University Bladder Cancer Tissue/Data Prospective Registry, funding from the U.S. Department of Defense and the National Cancer Institute, as well as the OSUCCC – James and the PIIO, which provided programmatic and logistical support. Other co-authors from Ohio State include Tong Xiao; Timothy Gauntner, DO, PhD; Kyeong Joo Jung; Emily Fitts; Krishan Kumar, PhD; Ryan Elaoud; Kelsi Reynolds; Cheryl Lee, MD; Kamal Pohar, MD; Steven Clinton, MD, PhD; William Carson, PhD; and Dongjun Chung, PhD. Written by Margaret Rockwood Media Contact: Mary Ellen Fiorino, MaryEllen.Fiorino@osumc.edu