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Dextran Enhances the Lentiviral Transduction Efficiency of Murine and Human Primary NK Cells
Published on: January 15, 2018
Liposomal Oncolytic Adenovirus Enables Efficient CAR-Independent Transduction of Tumors and Enhances NK Cell-Mediated
Tao Dong1,2,3, Jaimin R Shah1,3,4, Abraham T Phung1,2,3
1Department of Medicine, Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0809, United States.
Abstract:
Effective delivery of oncolytic adenoviruses to tumors with low coxsackievirus and adenovirus receptor (CAR) expression remains a major barrier in oncolytic virotherapy. In this study, a liposome-encapsulated adenovirus serotype 5-based platform (DfA) was designed to bypass CAR-dependent transduction, presenting engaging antitumor immune responses in an innate immune, NK cell-dependent manner. The results show that DfA efficiently transduces CAR-low murine colorectal cancer cells (CT26) and triggers the release of damage-associated molecular patterns (DAMPs), including ATP, HMGB1, and calreticulin. In immunocompetent mice, intratumoral DfA treatment suppressed both local and distant tumor growth. In nude mice lacking T cells, DfA retained systemic antitumor activity, but abscopal effects were lost upon NK cell depletion, which suggests that natural killer (NK) cells are essential mediators of this response. In vitro, DfA enhanced NK92 cytotoxicity against low-CAR MCF-7 breast cancer cells, which further supports its innate immune-activating potential. Together, these findings reveal a previously unrecognized role for NK cells in mediating adenovirus-induced abscopal effects and position DfA as a clinically actionable strategy for CAR-deficient tumors.
Insights
Liposome-encapsulated adenovirus (DfA) effectively targets tumors lacking the coxsackievirus and adenovirus receptor (CAR). Natural killer (NK) cells are crucial for DfA
Area of Science:
- Oncolytic virotherapy
- Immunology
- Nanomedicine
Background:
- Effective delivery of oncolytic adenoviruses is hindered by low coxsackievirus and adenovirus receptor (CAR) expression in tumors.
- CAR-dependent transduction limits the efficacy of adenovirus-based cancer therapies.
Purpose of the Study:
- To develop a CAR-independent adenovirus delivery platform (DfA) for enhanced oncolytic virotherapy.
- To investigate the role of innate immunity, specifically NK cells, in DfA-mediated antitumor responses.
Main Methods:
- Liposome-encapsulation of adenovirus serotype 5 to create the DfA platform.
- In vitro transduction assays with CAR-low cancer cell lines (CT26, MCF-7).
- In vivo studies in immunocompetent and nude mice to assess tumor suppression and abscopal effects, including NK cell depletion experiments.
Main Results:
- DfA efficiently transduced CAR-low colorectal cancer cells (CT26) and induced damage-associated molecular pattern (DAMP) release.
- Intratumoral DfA treatment suppressed local and distant tumor growth in immunocompetent mice.
- Systemic antitumor activity was observed in T cell-deficient mice, with abscopal effects dependent on NK cells.
Conclusions:
- DfA bypasses CAR-dependent transduction, enabling effective oncolysis in CAR-deficient tumors.
- Natural killer (NK) cells are essential mediators of DfA-induced systemic antitumor effects and abscopal responses.
- DfA represents a promising, clinically actionable strategy for treating CAR-deficient tumors by harnessing innate immunity.
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