Engagement of SIRPα Inhibits Growth and Induces Programmed Cell Death in Acute Myeloid Leukemia Cells

Abstract

BackgroundRecent studies show the importance of interactions between CD47 expressed on acute myeloid leukemia (AML) cells and the inhibitory immunoreceptor, signal regulatory protein-alpha (SIRPα) on macrophages. Although AML cells express SIRPα, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRPα in acute myeloid leukemia.Design and MethodsWe analyzed the expression of SIRPα, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRPα on two low SIRPα expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRPα expression on tumor cell growth and programmed cell death by its triggering with an agonistic antibody in these cells. Moreover, we examined the efficacy of agonistic antibody in combination with established antileukemic drugs.ResultsBy microarray analysis of an extensive cohort of primary AML samples, we demonstrated that SIRPα is differentially expressed in AML subgroups and its expression level is dependent on differentiation stage, with high levels in FAB M4/M5 AML and low levels in FAB M0–M3. Interestingly, AML patients with high SIRPα expression had a poor prognosis. Our results also showed that SIRPα is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRPα with an agonistic antibody in the cells stably expressing chimeric SIRPα, led to inhibition of growth and induction of programmed cell death. Finally, the SIRPα-derived signaling synergized with the activity of established antileukemic drugs.ConclusionsOur data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML.

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

“…In the immune system binding of TSP1 to CD47 inhibits T cell activation (9–11), in part by inhibiting the autocrine activating function of hydrogen sulfide signaling in T cells (12). TSP1 is the relevant CD47 ligand in T cells because these cells do not express detectable levels of SIRPα (13, 14). Signaling through CD47 also regulates T cell differentiation and adhesion as well as NK and dendritic cell functions that regulate adaptive immunity (15–22).…”

CD47 protein expression in acute myeloid leukemia: A tissue microarray-based analysis

“…Alternative pathogenetic mechanisms in addition to inhibition of phagocytosis have been proposed to contribute to a worse clinical outcome: CD47-SIRP␣ signaling on dendritic cells (DCs) impairs their T-cell allo-stimulatory capacity by blocking DC maturation [7], whilst the role of SIRP␣-independent triggering of CD47 to induce caspase-independent programmed cell death as not been unanimously confirmed [4,8].…”

CD47, a multi-facetted target for cancer immunotherapy

“…In contrast to solid tumors, SIRPα is notably down-regulated in primary hematopoietic cells and myeloid blasts from AML patients (Seiffert et al, 1999). This downregulation may be related to the reported induction of apoptosis and growth inhibition by SIRPα in AML cells (Irandoust et al, 2013). Another important binding partner of CD47 is TSP-1, the first endogenous ligand identified for CD47.…”