Thursday, September 27, 2012
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.
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]).
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.
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).
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.
strategy could be to use mAbs that promote apoptosis of leukemia stem cells
upon binding to CD47 (II[c]).