Journal
BIOMATERIALS
Volume 189, Issue -, Pages 48-59Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.10.022
Keywords
MDSC; Immunosuppression; Tumor microenvironment; Nanoparticle; Gemcitabine
Funding
- National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) Advance-CTR pilot grant [U54GM115677]
- Rhode Island Foundation Medical Research Fund [20164344]
- COBRE [NIH P20 GM104317]
- Lifespan Molecular Pathology Core
- URI Genomics and Sequencing Center
- [R01GM61988]
- [R01ES07965]
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Myeloid-derived suppressor cells (MDSCs) promote tumor-mediated immunosuppression and cancer progression. Gemcitabine (Gem) is a MDSC-depleting chemotherapeutic agent; however, its clinical use is hampered by its drug resistance and inefficient in vivo delivery. Here we describe a strategy to formulate a Gem analogue gemcitabine monophosphate (GMP) into a lipid-coated calcium phosphate (LCP) nanoparticle, and investigate its antitumor immunity and therapeutic effects after systemic administrations. In the syngeneic mouse model of B16F10 melanoma, compared with free Gem, the LCP-formulated GMP (LCP-GMP) significantly induced apoptosis and reduced immunosuppression in the tumor microenvironment (TME). LCP-GMP effectively depleted MDSCs and regulatory T cells, and skewed macrophage polarization towards the antitumor M1 phenotype in the TME, leading to enhanced CD8(+) T-cell immune response and profound tumor growth inhibition. Thus, engineering the in vivo delivery of MDSC-depleting agents using nanotechnology could substantially modulate immunosuppressive TME and boost T-cell immune response for enhanced antitumor efficacy.
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