Figure 1. Immune escape by leukemia stem cells and potential therapeutic strategies. Upregulation of CD47 expression is a strategy leukemia stem cells employ to escape the immune system.

(I) CD47 on leukemia stem cells engages with signal regulatory protein-a (SIRPA) on macrophages to convey a 'don't eat me' signal (I[a]). These leukemia stem cells engraft into host bone marrow, where they are able to give rise to leukemic blasts (I[b]).

(II) As reported in Theocharides et al., using a SIRPA-Fc fusion protein to disrupt the interaction between CD47 and SIRPA promotes macrophage-mediated phagocytosis of acute myelogenous leukemia (AML) stem cells and impairs their engraftment (II[a]). Other groups have shown that anti-CD47 mAbs also could have a similar effect.

Disrupting the CD47-SIRPA interaction also has the potential to enhance the killing of leukemia stem cells via Fc-dependent mechanisms (II[b]). For example, disrupting the CD47-SIRPA interaction might improve the effect of mAbs that promote antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC).

In ADCC, immune cells such as NK cells interact with the mAb and release factors (red circles) that lyse the leukemia stem cell. In CDC, binding of a mAb activates the complement cascade, which results in the formation of the membrane attack complex that causes cell lysis.

Another strategy could be to use mAbs that promote apoptosis of leukemia stem cells upon binding to CD47 (II[c]).