Abstract
CD47 is a cell-surface marker well recognized for its anti-phagocytic functions. As such, an emerging avenue for targeted cancer therapies involves neutralizing the anti-phagocytic function using monoclonal antibodies (mAbs) to enhance tumour cell immunogenicity. A lesser known consequence of CD47 receptor ligation is the direct induction of tumour cell death. While several mAbs and their derivatives with this property have been studied, the best characterized is the commercially available mAb B6H12, which requires immobilization for induction of cell death. Here, we describe a commercially available mAb, CC2C6, which induces T-cell acute lymphoblastic leukemia (ALL) cell death in soluble form. Soluble CC2C6 induces CD47-dependent cell death in a manner consistent with immobilized B6H12, which is characterized by mitochondrial deficiencies but is independent of caspase activation. Titration studies indicated that CC2C6 shares a common CD47-epitope with B6H12. Importantly, CC2C6 retains the anti-phagocytic neutralizing function, thus possessing dual anti-tumour properties. Although CD47-ligation induced cell death occurs in a caspase-independent manner, CC2C6 was found to stimulate increases in Mcl-1 and NOXA levels, two Bcl-2 family proteins that govern the intrinsic apoptosis pathway. Further analysis revealed that the ratio of Mcl-1:NOXA were minimally altered for cells treated with CC2C6, in comparison to cells treated with agents that induced caspase-dependent apoptosis which alter this ratio in favour of NOXA. Finally, we found that CC2C6 can synergize with low dose chemotherapeutic agents that induce classical apoptosis, giving rise to the possibility of an effective combination treatment with reduced long-term sequelae associated with high-dose chemotherapies in childhood ALL.
Highlights
Acute lymphoblastic leukemia (ALL) is the most commonly occurring childhood cancer, accounting for 25% of patients under 15 years old
Since CD47 exists in alternately spliced isoforms encoding different Cterminal cytosolic tails with unknown function, we assessed, and found that CC2C6-induced comparable cell death in CD47−/− cells expressing CD47-iso[1], iso[2] or iso[4], suggesting the cytosolic tail plays an insignificant role (Supp Fig. 2B)
We found that CC2C6-induced death was comparable for cells incubated in serum-containing or serum-free media, suggesting that serum thrombospondin as a CD47-ligand contributes minimally to the death-inducing effects (Supp Fig. 3A)
Summary
Acute lymphoblastic leukemia (ALL) is the most commonly occurring childhood cancer, accounting for 25% of patients under 15 years old. ALL is highly treatable, achieving a 5-year disease-free rate approaching 90%1. Disease treatment is stratified into low and highrisk therapies, with vincristine, corticosteroids, and asparaginase included in both, while anthracyclines are reserved for high-risk patients given their elevated toxicity[1]. Increased CD47-expression has been observed in a variety of tumour cells and considered an adverse prognostic factor[8]. It is the target of therapeutic intervention, achieved by antigen receptor neutralization using
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