Inhibition of SIRPα signaling promotes macrophage phagocytosis of LSCs but not normal HSCs.

  • Major finding: Inhibition of SIRPα signaling promotes macrophage phagocytosis of LSCs but not normal HSCs.

  • Approach: SIRPα–CD47 binding was disrupted with genetic SIRPα variants or a SIRPα–Fc fusion protein.

  • Impact: Targeting of SIRPα may enhance macrophage immune surveillance and LSC killing in human AML.

Immune surveillance is essential for the recognition and elimination of transformed cells, and cancer cell evasion of these mechanisms enables tumor growth and progression. However, the role of innate immune cell receptors in tumor surveillance is not well understood. Theocharides and colleagues hypothesized that signal regulatory protein α (SIRPα), which is expressed on macrophages and promotes normal hematopoietic stem cell (HSC) engraftment in xenotransplant models via interaction with its ligand CD47, may similarly regulate leukemia stem cells (LSC). To test this possibility, primary human acute myeloid leukemia (AML) cells were xenotransplanted into the bone marrow of congenic strains of immunodeficient mice expressing SIRPα variants. Lack of SIRPα binding to CD47 as a result of Sirpa polymorphism diminished AML engraftment and migration of AML cells to distant sites and impaired engraftment in serial transplant recipients, providing evidence that SIRPα modulates LSC function. Suppression of leukemic outgrowth in the absence of SIRPα–CD47 signaling was mediated by macrophages, as specific depletion of these cells alleviated the genetic restriction of AML engraftment and macrophages expressing a SIRPα variant unable to bind CD47 demonstrated increased phagocytosis of AML cells. These results were confirmed through disruption of the SIRPα–CD47 interaction with a human SIRPα-Fc fusion protein, which augmented the phagocytic activity of murine and human macrophages against AML cells and significantly decreased leukemic engraftment in treated mice. Importantly, the SIRPα-Fc fusion protein preferentially increased phagocytosis of AML targets by human macrophages but did not affect normal HSC function or survival, supporting the existence of a therapeutic window for agents that disrupt SIRPα–CD47 interactions. Although clinical trials are needed to evaluate the importance of this immune surveillance mechanism in patients, this study suggests that targeting the SIRPα–CD47 interaction may be beneficial in AML.

Theocharides AP, Jin L, Cheng PY, Prasolava TK, Malko AV, Ho JM, et al. Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts. J Exp Med 2012 Sept 3 [Epub ahead of print].