The Department of Biomedical & Chemical Engineering is pleased to welcome faculty candidate Dr. Jingjing Sun from the University of Pittsburgh in presenting her candidate seminar: “Ultrasmall Nanomedicine for Enhancing Tumor Penetration and Overcoming Pancreatic Cancer Immune Resistance”
Pancreatic ductal adenocarcinoma (PDAC) lacks effective therapeutic strategy due to its unique tumor microenvironment. The dense desmoplastic stroma not only restricts penetration of nanomedicine to the core of tumors, but also affects the infiltration of effector T cells, leading to an immunologically tolerant environment and driving treatment resistance. In this work, we designed an ultrasmall nanocarrier based on gemcitabine (GEM)-conjugated polymer PGEM, which exhibited selective accumulation and efficient penetration in various PDAC models. Moreover, different from most reported GEM-conjugated polymers, PGEM polymer could serve as a prodrug carrier to load a wide variety of hydrophobic agents with high drug loading capacity and excellent stability. Through RNAseq analysis, we also discovered that PGEM carrier could activate STING-Type I IFN innate immune response. However, activation of STING signaling is double-edge sward, which also drove the induction of chemokines CCL2 and CCL7, resulting in immune resistance by recruiting tumor associated macrophage (TAM) and myeloid-derived suppressor cells (MDSCs). Through the combination of computer modeling and experimental screening, we developed a dual delivery modality by incorporating a CCR2 (the receptor shared by both CCL2 and CCL7) antagonist into PGEM nanocarrier system. The new nanomedicine significantly reduced pancreatic tumor burden and induced potent anti-tumor immunity through reversing the CCL2/CCL7-mediated immunosuppression. Moreover, the nanomedicine sensitized PDAC tumors to anti-PD-1 therapy, leading to complete suppression/eradication of the tumors. Our work has shed light to the multi-faceted role of STING activation and provided a novel immunotherapy regimen to maximize the benefit of STING activation for PDAC treatment.
For more information, contact Prof. Zhen Ma at email@example.com
This event was first published on January 23, 2023 and last updated on February 2, 2023.
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