Phagocytosis, the biological process that destroys foreign particles and removes dead cells from circulation, represents a fundamental function of the immune system. Facilitated by immune cells called phagocytes that ingest (or phagocytose) foreign substances, phagocytosis can enhance the immune response, making it an attractive focus of research aiming to improve anti-tumor immunity.
Macrophages represent one type of phagocytic cells that play an important role in controlling cancer by phagocytosing tumor cells. Cancer cells display markers called “eat me” signals, which bind to macrophage receptors. Engagement of these molecules initiates phagocytosis.
To prevent being eliminated by macrophages, some cancer cells upregulate a molecule called C47 on their surface. CD47, a “don’t eat me” signal, inhibits phagocytosis by activating a receptor known as signal regulatory protein α (SIRPα) on macrophages. Many normal cells express CD47; thus, the absence of CD47 on damaged cells facilitates removal. Cancer cells have evolved to upregulate CD47, thus tricking macrophages into forgoing removal.
While drugs that block CD47 have shown promise for cancer treatment, because CD47 shows up on so many non-cancer cells, the resulting side effects remain a challenge. A recent study published in Nature Immunology further investigated the shortcomings of CD47 blockade and identified a more specific target that harnesses the anti-tumor benefits while sparing some of the associated toxicities.
The study shows that CD47 enacts two distinct mechanisms to suppress phagocytosis. In addition to activating the macrophage receptor SIRPα, CD47 also interacts with a ligand called SLAMF7. Unlike CD47, most healthy cells do not express SLAMF7, making it relatively unique to cancer cells.
The researchers showed that the CD47 blockade prevented interaction with SLAMF7. The study also introduced a pharmaceutical agonist of SLAMF7 (Z10), which blocked SLAMF7 activity but did not interfere with SIRPα signaling. Z10, in combination with an inhibitor of SIRPα, induced markedly better tumor control in pre-clinical mouse lymphoma models. This combination had greater anti-tumor efficacy than CD47 blockade.
The discovery of the SIRPα-independent mechanism by which CD47 can inhibit phagocytosis adds a novel pathway for future investigation and drug targeting. Additionally, the study provides a rationale for further investigation of Z10 as an anti-cancer agent in clinical trials.
Sources: Nat Rev Cancer, NEJM, Nat Immunol, NCI Visuals Online