Innate Immune Cytosolic DNA Sensors as Novel Protumorigenic Drivers in Stomach Cancer
Abstract
Stomach cancer (also known as gastric cancer GC) - the Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of our proposed research - is the third most lethal cancer worldwide, and has a poor 5-year survival rate of approximately 25%. This is largely due to both the late detection of disease and limited effectiveness of current chemotherapy. The pathogenesis of most GC cases is caused by chronic inflammation resulting from uncontrolled activation of the body’s two arms of the immune system: innate immunity, which is the first line of defense against foreign agents (e.g., bacterial pathogens) and tissue injury that triggers a rapid, non-specific immune response; and adaptive immunity, which mounts a slower, highly specific immune response. However, current immune-based treatments for GC patients have only focused on a select few adaptive immune checkpoint inhibitors (e.g., anti-PD-L1) which have yielded limited clinical benefits. Therefore, there is an urgent need to identity new genes of the immune system, in particular innate immunity (which remains underexplored), that can serve as therapeutic drug targets in GC. Uncontrolled activation of innate immunity is triggered by various environmental GC risk factors, such as infection with the gastric bacterial pathogen H. pylori, as well as excessive alcohol consumption and exposure to biomass and tobacco smoke, and ionizing radiation. Notably, active U.S. military personnel and Veterans, with a bias towards males, are exposed to high levels of these GC risk factors during military deployments compared to the North American civilian population. Therefore, military Service Members are at a higher long-term risk of developing GC. However, it remains unknown how these military relevant risk factors for GC interact with genes of the (innate) immune system in certain individuals to cause GC. Accordingly, the rationale for our proposal is driven by the urgent and unmet clinical need to identify new cancer-causing genes of the immune system that will serve as both novel biomarkers (for instance, prognostic of survival outcomes and predictive of treatment responses and/or individuals who are most susceptible of developing GC upon exposure to environmental military risk factors (e.g., H. pylori)), and therapeutic targets for treatment strategies. In this regard, our proposal has a direct impact on the FY21 PRCRP Military Health Focus Areas Environmental exposure risk factors associated with cancer and Mission Readiness - Gaps in cancer early detection/diagnosis, prognosis and/or treatment. To address these substantial knowledge gaps in GC, our scientific objective is to demonstrate that a family of genes of the body’s immune system, called cytosolic DNA sensors, plays a critical role in promoting GC. Cytosolic DNA sensors detect intracellular DNA from both invading bacteria (such as H. pylori) and the individual host, such as damaged DNA in stomach cells caused by exposure to military risk factors (e.g., smoke, ionizing radiation). Although cytosolic DNA sensors are best known for initiating immune responses in the context of infectious, inflammatory and autoimmune diseases, their role in cancer is poorly understood, and in GC is completely unknown. Notably, hallmarks of GC patients are cancer-inducing cellular DNA damage and H. pylori infection, and our supporting data show that the expression of specific cytosolic DNA sensors is highly upregulated in response to H. pylori and in GC patients, the latter associating with poor survival. Therefore, our innovative idea is that specific cytosolic DNA sensors are highly activated in the stomachs of U.S. active-duty military personnel and Veterans with higher exposure to GC risk factors (e.g., H. pylori) that cause DNA damage. The identification of innate immune cytosolic DNA sensors as key pro-tumorigenic host sensors of H. pylori and cellular DNA damage in the stomach will introduce a new paradigm o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210394
Entities
People
- Brendan J. Jenkins
Organizations
- Monash University
- United States Army