Nanoengineering Immune Cells to Target Therapeutics to the Tumor Microenvironment
Loading...
Date
2020-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
The Ohio State University
Abstract
The tumor microenvironment (TME) plays a key role in the development and aggressiveness of solid tumors, which poses significant challenges to effective cancer treatment. The TME is a complex and dynamic niche involving a network of tumor, stromal and infiltrating immune cells. Crosstalk among these TME components orchestrate a variety of tumor-promoting and -protective mechanisms that enable solid tumor evasion from various internal and external therapeutic effects. Such behaviors include driving angiogenesis in tumors, inducing an immunosuppressive niche, and supporting the invasion and metastasis of tumor cells.
Emerging cancer treatment strategies look to target the malignant features of the TME in efforts to improve therapeutic outcome to solid tumors. However, treatment modalities are limited by the difficulties in overcoming physiological barriers to localize and infiltrate therapy to tumors.
A potential key to achieving effective therapeutic delivery to tumors may reside with immune cells found in the TME, the myeloid-derived suppressor cell (MDSC). MDSCs are a heterogenous population of immature immune cells known for their immunosuppressive activity in tumors. However, our recent studies have revealed MDSCs are also uniquely characterized with an innate tumor tropism. We hypothesize that by exploiting MDSC localization to tumors, MDSCs engineered with anti-cancer targets can serve as stealth delivery vehicles to effectively target therapeutic payloads to the TME.
Here, we applied nanoengineering strategies to equip MDSCs with tissue inhibitor of metalloproteinase-3 (TIMP-3), a tumor suppressor gene with various roles in regulating carcinogenesis in tumors, such as inhibiting the migration and invasion of tumor cells. Nanoengineered MDSCs (NE-MDSCs) were transfected with TIMP-3 using electroporation and evaluated on their potency to tumor cells in-vitro and ability to deliver therapeutic cargo of TIMP-3 to tumors in-vivo upon systemic injection to mouse models of breast cancer.
Transfection significantly increased expression of TIMP-3 gene target in NE-MDSCs after 24 hours (p=0.0001). NE-MDSCs were observed to exert anti-metastatic effects of TIMP-3 to tumor cells in co-culture, by driving a trend toward inhibiting tumor cell invasion. Systemic administration of NE-MDSCs to tumor-bearing mice revealed NE-MDSCs honing to tumors, and successfully drove an increase in TIMP-3 gene and protein expression levels intratumorally. The preliminary results here demonstrate the promising potential of NE-MDSCs as means to target therapeutic delivery to influence the TME. Future studies should look to continue on developing and improving NE-MDSC stealth technology to advance its clinical applications.
Description
Keywords
tumor microenvironment, targeted cancer therapy, cellular vehicles, gene therapy, myeloid-derived suppressor cells