Novel Immunonanoengineering Strategy to Overcome Neutrophil-Mediated Stromal Inflammation and Therapy Resistance in Pancreatic Cancer
Abstract
Pancreatic cancer is a lethal malignancy refractory to standard chemotherapy due to intrinsic and acquired therapeutic resistance. The key culprits associated with therapeutic resistance are (1) early and frequent infiltration of tumors by immunosuppressive innate immune cells, particularly neutrophilic myeloid-derived suppressor cells (MDSC); and (2) pro-tumorigenic signaling by cancer-associated fibroblasts (CAF), which dominate the non-tumor stroma and act as cellular antennae to transmit inflammatory cues that further beckon MDSCs to the tumor microenvironment. In dissecting the unifying mechanisms that underpin the relationship between MDSC-CAF communication and chemoresistance in pancreatic cancer, our data uncover inflammasome activation in MDSCs -- culminating with the release of IL-1-beta, a pro-inflammatory cytokine -- as a previously unrecognized regulator of inflammatory CAF development in the tumor microenvironment. Interestingly, dampening global inflammasome activation with a novel pharmacologic inhibitor in mouse models of pancreatic cancer underscored the crucial importance of restricting inflammasome inhibition specifically to the MDSC compartment, in order to spare immunostimulatory effects of inflammasome activation in antitumor dendritic cells and T cells. Building on these observations, the overall mission of this proposal is twofold: (1) to mechanistically delineate the pathogenic role of MDSC-restricted inflammasomes in instigating stromal inflammation in the pancreatic tumor microenvironment; and (2) catalyze development of a bold nanoengineered immunotherapy to disrupt inflammasome activation solely in neutrophilic MDSCs to overcome chemoresistance in pancreatic cancer. The first aim -- addressing the PCARP Focus Area relating to oncogenic signaling in the tumor microenvironment -- will interrogate the effects of context-specific silencing of MDSC-derived inflammasome activation on CAF evolution using innovative preclinical mouse modeling and single-cell methodologies. The second aim, utilizing a unique high-dimensional tissue imaging platform, will uncover whether precise spatial relationships between these inflammasome-enriched MDSC-CAF communities in human pancreatic tumors can predict poor chemotherapy responses in patients receiving treatment in our clinics. Moreover, we will investigate if the density of these MDSC-CAF neighborhoods is disproportionately concentrated in pancreatic tumors from Black patients, in an attempt to discover tissue-level molecular insights that explain racial disparities observed with chemotherapy responses in pancreatic cancers from Black patients. The latter will address another PCARP Focus Area related to underserved ethnic/minority communities. The third aim will offer a conceptual breakthrough in the therapeutic landscape of pancreatic cancer by proposing a novel neutrophil-homing nanoparticle that can deliver inhibitors of inflammasome activation with incredible precision solely to neutrophilic MDSCs. Leveraging this technology, we will determine if this innovative strategy mitigates stromal inflammation but spares (and even augments) antitumor immunity to improve chemosensitivity in pancreatic cancer models. This will address another PCARP Focus Area related to new drug discovery targeting immune mechanisms of resistance. Ultimately, successful completion of this proposal will not only advance our understanding of contextually sensitive signaling circuitry in the tumor microenvironment that underlies therapeutic resistance in pancreatic cancer, but also lay the groundwork for commercialization and human translation of our novel MDSC-directed immunonanotherapeutic approach to improve chemosensitivity in patients afflicted with this lethal disease. To demonstrate our commitment to human translation, we have assembled a collaborative team with an outstanding track record of bringing promising cancer nanotherapeutics to fruition. Given the urge
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310699
Entities
People
- Jashodeep Datta
Organizations
- United States Army
- University of Miami