D.E. Discher
University of Pennsylvania,
United States
Keywords: circulation, macrophage, CD47
Summary:
Particles of any type interact with innate immune phagocytes while nearby ‘Self’ cells are spared. The ubiquitously expressed membrane protein CD47 was identified first on RBCs as a protein that limits splenic clearance of circulating cells, which are of course large and flexible cells. Display of CD47 or its fragments on synthetic nanoparticles and on viruses likewise delay clearance of these much smaller entities [1, 2]. With lentivectors, for example, single particle analyses show properly oriented human-CD47 for interactions with the macrophage’s inhibitory receptor SIRPA. Macrophages derived from humans and 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 vivo transduction of spleen and liver macrophages also decreases for hCD47-Lenti while transduction of lung carcinoma xenografts increases. Other groups have already begun injecting anti-hCD47 in trials with cancer patients and generally observe loss of blood cells and some promising effects on tumors. Such clinical trial results are consistent not only with blockade of this macrophage checkpoint but also with its application on nanoparticles and viruses. References: [1] Rodriguez, et al. Minimal 'Self' peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science (2013). [2] Sosale, et al. “Marker of Self” CD47 on lentiviral vectors decreases macrophage-mediated clearance and increases delivery to SIRPA-expressing lung carcinoma tumor. Molecular Therapy – Methods & Clin Development (2016).