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Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

Johanna TheruvathMarie MenardBenjamin A H SmithMiles H LindeGarry L ColesGuillermo Nicolas DaltonWei WuLouise KiruAlberto DelaidelliElena SotilloJohn L SilbersteinAnna C GeraghtyAllison BanuelosMolly Thomas RadosevichShaurya DhingraSabine HeitzenederAidan TousleyJohn LattinPeng XuJing HuangNicole NasholmAndy HeTracy C KuoEmma R B SangalangJaume PonsAmira BarkalRachel E BrewerKristopher D MarjonJose G Vilches-MourePayton L MarshallRicardo FernandesMichelle MonjeJennifer R CochranPoul H SorensenHeike Elisabeth Daldrup-LinkIrving L WeissmanJulien SageRavindra MajetiCarolyn R BertozziWilliam A WeissCrystal L MackallRobbie G Majzner
Published in: Nature medicine (2022)
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.
Keyphrases
  • small cell lung cancer
  • poor prognosis
  • mouse model
  • induced apoptosis
  • drug delivery
  • cell death
  • free survival
  • cell cycle arrest
  • endoplasmic reticulum stress