Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by intratumoral abundance of neutrophilic/polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) which exert anti-T-cell functions through multiple mechanisms, especially JAK2/STAT3-regulated arginase activity. To overcome limitations of systemic inhibition of PMN-MDSCs in cancer-bearing patients such as neutropenia and compensatory myelopoietic adaptations, we developed a nanoengineering strategy to disrupt cell-specific signaling exclusively in PMN-MDSCs without compromising viability or provoking neutropenia. Single-cell RNA sequencing in human/murine PDAC, and flow cytometry in peripheral blood cells from treatment-naïve PDAC patients, nominated surface receptor CXCR2 as a PMN-MDSC-exclusive target. We chemically modified a small-molecule CXCR2 inhibitor AZD5069 by conjugating it with polyethylene glycol (PEG) to enhance aqueous solubility. This AZD5069-PEG construct was then chemically grafted onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Cy5.5 dye-loaded CXCR2-NPs showed near-exclusive uptake in PMN-MDSCs compared with Kras
;p53
;Pdx1
(KPC) PDAC tumor cells, KPC cancer-associated fibroblasts, macrophages, and dendritic cells. Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NP
) resulted in more efficient and durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs as well as robust induction of cytolytic T-cell activity compared with free Ruxolitinib in vitro and in orthotopic tumor cell-CAF co-injection models in vivo. Treatment of orthotopic tumor-bearing KPC mice with CXCR2-NP
reduced tumor burden compared with vehicle, free Ruxolitinib, or non-drug-loaded CXCR2-NP treatments, without causing appreciable neutropenia. Taken together, cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC.