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Theruvath, Johanna; Menard, Marie; Smith, Benjamin A H; Linde, Miles H; Coles, Garry L; Dalton, Guillermo Nicolas; Wu, Wei; Kiru, Louise; Delaidelli, Alberto; Sotillo, Elena; Silberstein, John L; Geraghty, Anna C; Banuelos, Allison; Radosevich, Molly Thomas; Dhingra, Shaurya; Heitzeneder, Sabine; Tousley, Aidan; Lattin, John; Xu, Peng; Huang, Jing; Nasholm, Nicole; He, Andy; Kuo, Tracy C; Sangalang, Emma R B; Pons, Jaume; Barkal, Amira; Brewer, Rachel E; Marjon, Kristopher D; Vilches-Moure, Jose G; Marshall, Payton L; Fernandes, Ricardo; Monje, Michelle; Cochran, Jennifer R; Sorensen, Poul H; Daldrup-Link, Heike E; Weissman, Irving L; Sage, Julien; Majeti, Ravindra; Bertozzi, Carolyn R; Weiss, William A; Mackall, Crystal L; Majzner, Robbie G
Nature medicine, 02/2022, Letnik: 28, Številka: 2Journal Article
The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2 malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.
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in: SICRIS
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