title: "Marker of Self" CD47 on lentiviral vectors decreases macrophage-mediated clearance and increases delivery to SIRPA-expressing lung carcinoma tumors.
abstract: Lentiviruses infect many cell types and are now widely used for gene deliveryin vitro, butin vivouptake of these foreign vectors by macrophages is a limitation. Lentivectors are produced here from packaging cells that overexpress "Marker of Self" CD47, which inhibits macrophage uptake of cells when prophagocytic factors are also displayed. Single particle analyses show "hCD47-Lenti" display properly oriented human-CD47 for interactions with the macrophage's inhibitory receptor SIRPA. Macrophages derived from human and NOD/SCID/Il2rg-/-(NSG) mice show a SIRPA-dependent decrease in transduction,i.e., transgene expression, by hCD47-Lenti compared to control Lenti. Consistent with known "Self" signaling pathways, macrophage transduction by control Lenti is decreased by drug inhibition of Myosin-II to the same levels as hCD47-Lenti. In contrast, human lung carcinoma cells express SIRPA and use it to enhance transduction by hCD47-Lenti- as illustrated by more efficient gene deletion using CRISPR/Cas9. Intravenous injection of hCD47-Lenti into NSG mice shows hCD47 prolongs circulation, unless a blocking anti-SIRPA is preinjected.In vivotransduction of spleen and liver macrophages also decreases for hCD47-Lenti while transduction of lung carcinoma xenografts increases. hCD47 could be useful when macrophage uptake is limiting on other viral vectors that are emerging in cancer treatments (e.g., Measles glycoprotein-pseudotyped lentivectors) and also in targeting various SIRPA-expressing tumors such as glioblastomas.
authors.affiliation: Biophysical Engineering Labs, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Nisha G
authors.initials: NG
authors.lastname: Sosale
authors.affiliation: Biophysical Engineering Labs, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Irena I
authors.initials: II
authors.lastname: Ivanovska
authors.affiliation: Biophysical Engineering Labs, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Tsai
authors.affiliation: Biophysical Engineering Labs, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Swift
authors.affiliation: Biophysical Engineering Labs, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Jake W
authors.initials: JW
authors.lastname: Hsu
authors.affiliation: Pharmacological Sciences Graduate Group, University of Pennsylvania , Pennsylvania, USA.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Alvey
authors.affiliation: Children's Hospital of Philadelphia , Philadelphia, Pennsylvania, USA.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Zoltick
authors.affiliation: Biophysical Engineering Labs, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Pharmacological Sciences Graduate Group, University of Pennsylvania, Pennsylvania, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher