Self and non-self-recognition has always fascinated researchers in immunology, particularly when it comes to developing cancer immunotherapy as cancer cells often disguise themselves as “self” to evade the immune system. The “Don’t Eat Me” signal is probably one of the most-studied self-recognition signals in innate immunity, which is essentially described as the membrane-bound molecule CD47 presented by tissue cells. CD47 binds to the signal regulatory protein alpha (SIRPα) on macrophages, which leads to the phosphorylation of immunoreceptor tyrosine-based inhibition motif (ITIM) on the cytoplasmic tail of SIRPα and subsequent binding and activation of SHP-1 and SHP-2 molecules to block phagocytosis by preventing the accumulation of myosin-IIA at the phagocytic synapse[1]. CD47, on the other hand, is overexpressed on many types of solid tumor cells, blocking which has shown promising therapeutic effects against human tumors in mouse models. A therapeutic anti-CD47 monocloncal antibody, Hu-5F9-G4, is currently in phase I clinical trial in the US for treatment of cancers of lymphoid origin and was expected to be completed in August 2017. While the outcome of this study awaits to be published, other anti-CD47 immunotherapy options are fast becoming a popular immune checkpoint target for myeloid-originated tumors by several pharmaceutical and biotech companies world-wide.
As it turns out there seems to be a “back-up” plan for this CD47-SIRPα strategy in the human immune system, which can serve as a new promising target for cancer therapy. A recent publication in Nature2 by Weissman’s laboratory in Stanford University School of Medicine reported the identification of the second “Don’t Eat Me” signal, namely “MHC class I-LILRB1 (Leukocyte Immunoglobulin-Like Receptor B1)[2]. In in vitro and mouse models studies, LILRB1-expressed on the surface of macrophages and previously found to be an immune response modulator- was demonstrated to bind to a portion of the MHC class I molecule on cancer cells and to inhibit the ability of macrophages to engulf and kill cancer cells. Given that some cancer cells show lower expression of MHC class I proteins to help them escape T cell destruction, these cancer cells may be more vulnerable to anti-CD47. Conversely, as evident in the mouse model used in this study, targeting LILRB1 or MHC class I may improve cancer cells clearance when MHC class I protein is highly expressed.
As the first author of this study, Barkal, said “the fact that there are at least two redundant mechanisms to modulate macrophage activity is a testament to how critically important it is to tightly control our immune responses3.” So the discovery of this plan B not only opens up new avenues for developing anti-cancer therapeutics, but also encourages the search for potentially more pathways of similar nature.[3]
