Sex-Specific Immune Biomarkers of Bladder Cancer
Abstract
Scope of the Problem: Every year, 80,000 people in the U.S. are diagnosed with bladder cancer. Each and every patient with bladder cancer faces tremendous challenges. Patients with non-invasive tumors are subject to lifelong procedures (cystoscopy) for surveillance and to remove recurrent tumors. Medications given in the bladder (such as BCG) can require dozens of appointments year after year. For patients with invasive tumors, the standard treatment (surgical removal of the bladder, or radical cystectomy) is morbid, with a 60% complication rate and 4% mortality rate. This procedure also leads to permanent alterations in quality of life. For patients with advanced bladder cancers, even with modern chemotherapies or immunotherapies, survival is 1-2 years. Adding to the problem, 75% of bladder cancer cases are diagnosed in males. This is not explained by conventional bladder cancer risk factors like smoking. For unknown reasons, males shoulder a disproportionate burden from this disease. Background: Recent work suggests that the bladder cancer sex disparity is related to sex hormones (androgens such as testosterone). Our data in mouse models analyzed T cells (immune cells that have the ability to kill cancer cells) and found that T cells in males were “exhausted” (or unable to kill cancer cells), while T cells in females were “effectors” (that still had anti-tumor activity). Looking deeper, we found that the male T cells were exhausted because of hormonal signaling, with androgens signaling through a molecule called TCF1. We have begun to look at clinical bladder cancer samples from patients, and the tumor-infiltrating immune cells mirror what we have observed in the mouse model, so the findings appear to translate. We have even begun to see that immune cells in the urine of patients with bladder cancer reflects what is happening in their actual tumors. To the extent that tumor-infiltrating immune cells can tell us about a patient’s prognosis and response to therapy, we are making progress toward a non-invasive sex-specific biomarker as well. Objective: In this project we will test our findings in a rigorous mouse model (“BBN”) that is arguably the best pre-clinical model of human bladder cancer. Using traditional methods (flow cytometry) and modern genomics (single-cell RNA Sequencing), we will be able to validate the prevalence of exhausted T cells in male bladder cancers and also discover novel immune cell subsets. Leveraging Ohio State’s Bladder Cancer Tissue Registry, we will perform similar studies in clinical samples from patients and link our findings to sex and specific tumor features like stage, grade, and prior therapies. As part of this, we will perform urine/tumor association studies to precisely define the ways in which urine can be used as a non-invasive immune BlCa biomarker. Principal Investigator’s (PI’s) Cancer Research Goals: Dr. Sundi’s mission is to improve immune-based treatments for people with bladder cancer. As a bladder cancer surgeon, Dr. Sundi is all too familiar with the profound impact of the disease on patients, and this is what motivates him to advance research in this area. The proposed project will directly benefit patients with bladder cancer. A deeper understanding of the immune basis of the bladder cancer sex disparity will help physicians treat patients precisely with biomarker-driven medicines to optimize clinical outcomes. Career support from this award will also ensure Dr. Sundi has time protected from clinical duties at this early career stage and solidify his footing as a bladder cancer researcher with the ability to make long-term contributions to scientific advances for patients with this disease. Applicability: Altogether these aims will advance our understanding of bladder cancer, give us insights to decrease the bladder cancer sex disparity, and open the door for non-invasive testing to improve disease monitoring and precision treatments for all patients with the d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110636
Entities
People
- Debasish Sundi
Organizations
- Ohio State University
- United States Army