Targeting Innate Immune Inflammasomes as Key Drivers of Microbial-Associated Pancreatic Cancer and Therapy Resistance
Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents ~90% of all cases of pancreatic cancer, and is associated with a very low 5-year survival rate of only 9%-10%. This is largely due to late detection and limited efficacy of chemotherapy, with the latter compromised by chemoresistant tumors. PDAC is caused by gene mutations in the pancreas, as well as chronic inflammation resulting from uncontrolled activation of the body s two arms of the immune system: innate immunity, which is the first line of defence 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. Current immune-based treatments for PDAC patients have only focused on a select few adaptive immune checkpoint inhibitors (e.g., anti-PD-L1). Unfortunately, this approach has yielded limited clinical benefit. A key role for innate immunity in PDAC is suggested by the seminal finding that PDAC tumors house distinct gut-derived bacteria that promote tumor growth and can confer chemoresistance to gemcitabine, a cornerstone chemotherapy drug for PDAC over the last few decades. However, the mechanisms by which bacteria interact with innate immity to influence PDAC and chemoresistance are unknown. Therefore, there is an urgent need to identity new genes of the immune system, in particular innate immunity (which is underexplored), that can serve as therapeutic drug targets and biomarkers in PDAC. Our research proposal aims to address these substantial knowledge gaps by revealing that a distinct multiprotein complex of the innate immune system called the inflammasome promotes PDAC and chemoresistance. Core components of the inflammasome complex are the essential adaptor protein ASC and enzymatic protein Caspase-1, along with a specific pattern recognition receptor protein that detects ligands of microbial (e.g., bacteria) and host (e.g., from damaged cells) origins. Activation of the inflammasome controls the release of biologically active pro-inflammatory cytokines, IL-18 and IL-1ß, to modulate many inflammatory responses, as well as other cellular processes including cell death and proliferation. However, the role of inflammasomes in PDAC is unknown. Our compelling preliminary data lead us to hypothesize that microbial-sensing ASC inflammasomes are novel drivers of PDAC and chemoresistance. Therefore, our proposal addresses the FY21 PCARP Focus Areas of Understanding precursors, origins and early progression of pancreatic cancer and New drug development targeted toward cancer sensitivity and resistance mechanisms including immune mechanisms of resistance. Innovation: The role of ASC inflammasomes in cancer is ill-defined, and it is unknown whether ASC functions intracellularly or extracellularly, which may explain the contrasting pro- and anti-tumorigenic functions of ASC in some cancers. This knowledge is critical to inform whether ASC-directed drugs should increase or decrease its activity in a specific cancer. Our discovery that ASC inflammasomes drive tumorigenesis and chemoresistance in PDAC is conceptually innovative since it provides the first mechanistic explanation of how the innate immune system (via microbial-sensing ASC inflammasomes) facilitates interactions with tumor-promoting gut bacteria in cancer. Furthermore, using an anti-ASC nanobody that selectively blocks the activity of extracellular ASC inflammasomes will define the mode of action by which ASC inflammasomes promote PDAC and chemoresistance, and be the first time a specific ASC inhibitor is therapeutically evaluated in cancer. Also, our innovative study design, using patient-derived organoids and xenografts generated from EUS FNA biopsies (capturing all stages of PDAC), enables us to study ASC inflammasomes in chemoresistant late stage tumors. Impact: In the short term (< 5 years), our findings will reveal vital mechanistic knowl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211026
Entities
People
- Brendan J. Jenkins
Organizations
- Monash University
- United States Army