Authors:

Lara Mocan

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About Paper:

Natural Killer (NK) cells mediate antibody-dependent cellular cytotoxicity through CD16 (FcyRIll) [1]. However, upon activation, CD16 is cleaved from the NK cell surface via the ADAM17 metalloprotease [2], reducing cytotoxic activity. Inhibition of ADAM17 via TNF Protease Inhibitor 2 (TAPI-2) has been shown to block shedding of CD16 and enhance NK cell function. However, as ADAM17 is present on many cell types, this approach lacks cellular specificity. We hypothesized that bispecific lipid vesicles encapsulating TAPI-2 could enable activation-dependent local inhibition of CD16 cleavage in addition to increasing cancer cell lysis. Vesicles were engineered with surface-conjugated CD16 and HER2 antibodies via SNAP and Halo tags to promote simultaneous engagement of NK cells and HER2+ cancer cells. We proposed that NK cell activation through CD16 engagement leads to perforin release, inducing vesicle membrane permeability and localized TAPI-2 release, therefore inhibiting ADAM17 mediated CD16 shedding. Using flow cytometry, we evaluated CD16 surface expression on NK cells following receptor activation in the presence of soluble TAPI-2 or TAPI-2 encapsulated bispecific vesicles. TAPI-2 presence significantly reduced CD16 shedding relative to controls. Ongoing studies are assessing the impact of TAPI-2 encapsulated bispecific vesicles on cancer cell lysis. This research introduces a vesicular platform to enhance NK cell cytotoxicity and activity, as well as increase cancer cell lysis, by coupling cancer-specific activation and localized inhibition of CD16 cleavage, proposing a novel synthetic biology strategy to enhance NK cell mediation cancer cell lysis.

Source:

Northwestern University

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No topics listed

Co-authors:

Lara Mocan