The innate immune system is essential for rapid and efficient tumor surveillance. Certain types of white blood cells called Natural Killer cells, or NK cells, are promptly mobilized during the early stage of tumor development in order to control tumor growth through several mechanisms. These include production of molecules that limit tumor growth, direct killing of tumor cells, and prevention of their spread. Our laboratory has recently demonstrated that the NK cells found in human bladder cancers, are severely compromised functionally, in both early, non-invasive, as well as more advanced invasive tumors. We speculate that cancer cells and their environment adversely impact NK cell function, thereby compromising the ability of these cells to contain bladder tumor growth. Of significance, we have identified at least two target molecules that alter normal NK cell function and that will be a focus of the proposed studies. In this application, a clinical and research team of investigators with expertise in bladder cancer, innate immunity and immuno-oncology will (a) comprehensively characterize the nature of these dysfunctional NK cells from the tumors and blood of bladder cancer patients who have non-muscle invasive (NMI) and muscle invasive disease (MI); (b) identify the mechanisms underlying NK cell dysfunction in progressively growing tumors, and (c) design rational, preclinical interventions to enhance NK function and reverse NK dysfunction. This study addresses two FY18 PRCRP Topic Areas: Bladder Cancer and Immunotherapy. Our preliminary and proposed work will advance both areas by: 1. Understanding the process by which bladder tumors prevent the optimal, anti-tumor functionality of NK cells, and 2. Testing strategies to interfere with this process by using cells from the peripheral blood and tumor tissue of patients with bladder cancer. Ideally, we anticipate clinical trials to begin 1-2 years after completion of this proposal. This study also addresses the FY18 PRCRP Military Relevance Focus Area of further understanding militarily relevant risk factors associated with cancer. In March 2016, the National Academy of Medicine identified a possible link between exposure to Agent Orange and an increased risk of bladder cancer. This places US veterans who served during the Vietnam conflict at a higher risk than other groups. Additionally, improvements in the ability to detect and reverse NK cell dysfunction in individuals with bladder cancer will likely inform the therapeutic approaches taken for patients with other malignancies. As a result, these studies have potential to improve the health and well-being of our active service members, our veterans, and the general public.
|Effective start/end date||15/07/19 → 15/07/19|
- U.S. Army: $1,584,753.00