Regulation of Cell Intrinsic Immunity in Bladder Cancer

Scientific Objectives and Rationale:

Over 80,000 people are diagnosed every year in the United States with bladder cancer, and it is the fourth most commonly diagnosed malignancy in American Veterans. Advanced bladder cancer is often deadly, and survival rates even following aggressive treatment are low. While the development of immune oncology (IO)-based approaches for treatment of bladder cancer has improved this outlook, in reality only a small subset (approximately 15%-20%) of patients benefit. Therefore, there is a desperate need to identify patients most likely to respond to IO treatment, as well as increase the response rates following IO treatment in patients with advanced bladder cancer.

Expression of the protein programed death-ligand 1 (PD-L1) within the tumor is used as a biomarker to determine the likelihood that IO treatment will be effective. However, it is universally recognized that PD-L1 is at best a suboptimal predictive biomarker. This is partly because expression of PD-L1 is dynamic in cancer cells, meaning it can change over time. Identifying mechanisms important for the stable activation of PD-L1 expression in bladder cancer will enhance the identification of patients likely to benefit from IO treatment.

In addition to being a biomarker, PD-L1 is a therapeutic target for several clinically approved IO approaches. Interestingly, PD-L1 is but one member of a large family of interferon-responsive genes (ISGs). Like PD-L1, expression of these ISGs may predict response to IO. However, ISG expression is also dynamic. Identification of mechanisms required for the stable regulation of ISGs has the potential to identify the next generation of predictive biomarkers and IO drug targets.

Findings included in this application show that a common genetic event in bladder cancer, namely reduced expression of FOXA1, results in increased expression of both PD-L1 and global activation of an ISG signature. Because FOXA1 controls PD-L1 and ISG expression via epigenetic mechanisms, we propose that increased PDL1 and/or ISG expression is stable over time following reduced FOXA1 expression. Studying the epigenetic regulation of PD-L1 and ISGs will (1) enhance our ability to reliably predict who will respond to IO treatment, and (2) enable the identification of next-generation predictive biomarkers replacing PD-L1. To test these ideas, we propose first to use a battery of preclinical models to identify the impact of FOXA1 expression on several types of epigenetic changes associated with expression of PD-L1 and other ISGs in bladder cancer cells. Second, we will test the predictive value of PD-L1 and/or ISG-associated epigenetic changes in samples taken from patients undergoing IO treatment. Because epigenetic alterations in PD-L1 and ISGs following FOXA1 loss can repress the ability of the immune system to prevent cancer development, as a third step we will determine the impact of defined alterations on immune system function and responsiveness to IO treatment in living organisms.

Ultimate Applicability of Research:

Currently, our ability to identify patients who will respond to IO treatment is extremely limited, and patients are paying the price. Ideally, this proposal will result in the near-term (5 years) identification of new predictive biomarkers for IO and new IO therapeutic targets/treatment regimens. Identification of stable regulators of PD-L1 and other ISGs will also enhance clinical trial design in the next 5 years. In the longer term (7-10 years), successful completion of this research study holds the potential to provide avenues for the 'reprograming' of nonresponsive tumors to an IO-responsive state. By increasing the number of patients who benefit from the revolution in IO treatments, this would have a long-lasting impact on cancer care.

FY20 PRCRP Military Relevance Focus Area:

It has been said that 'a bad biomarker is as bad as a bad drug.' Ineffective biomarkers lead to overtreatment of patients who do not benefit, while patients who would benefit from treatment are never identified. While PD-L1 is a suboptimal biomarker, this proposal seeks to identify mechanisms contributing to the stability of PD-L1 expression, offering an opportunity to enhance its effective use. In addition, this proposal seeks to identify next generation predictive biomarkers for IO treatment. Because Veterans are at higher risk for developing advanced bladder cancer, successful completion of this proposal will enhance prognostication and the development of personalized treatment strategies. Therefore, the proposed project is relevant to active-duty Service Members, Veterans, and other military beneficiaries.