What is the importance of FcR engagement in the overall therapeutic efficacy of SIRPα–CD47 blockade?
What are the relative
Over the past decade, the use of blocking agents against inhibitory immune checkpoints (see Glossary) has been one of the most significant advances in anticancer treatment 1, 2, 3. These agents work on the general premise that immune cell functions are often suppressed in cancer and relief of this suppression improves antitumor immunity. Antibodies against inhibitory receptors expressed on T cells [such as cytotoxic T-lymphocyte-associated protein (CTLA)-4 and programmed death (PD)-1], or their
The exciting results obtained with CTLA-4 or PD-1 blockade led to evaluation of several additional immune checkpoints that could be targeted in anticancer treatment 1, 2, 3. One proposed target is signal-regulatory protein (SIRP)α, an inhibitory receptor expressed on myeloid cells, including macrophages, dendritic cells (DCs) and neutrophils (Figure 1) (for more detailed reviews, see 4, 5, 6, 7, 8, 9). SIRPα recognizes as ligand CD47, a receptor expressed on all normal cells, but often
One of the debates concerning SIRPα–CD47 blocking agents is whether sole blockade of the interaction between SIRPα and CD47 is sufficient to trigger phagocytosis and elimination of tumor cells by macrophages 4, 17, 18. The anti-CD47 antibodies, anti-SIRPα antibodies or soluble SIRPα proteins tested often contained an Fc portion, which could result in concomitant engagement of activating FcRs, thereby triggering phagocytosis (Figure 2 and Box 2). In the context of blockade of a potent inhibitory
Several studies have indicated that an adaptive immune response is critical to consolidate the impact of SIRPα–CD47 blockade on tumor growth in vivo. Tseng et al. showed that SIRPα–CD47 blockade augmented the ability of macrophages to stimulate antigen-specific CD8+ T cell, but not CD4+ T cell responses in vitro and in vivo [47]. These effects were obtained with Fc-bearing antibodies and correlated with better suppression of tumor growth in vivo. By contrast, it was reported that treatment of
An issue arising with the use of anti-CD47 antibodies is that these agents are likely to be sequestered away from tumor cells by the large pool of CD47 molecules expressed on normal cells. Such an effect was not estimated in studies of SIRPα–CD47 blockade using human tumor cells transplanted in mice, in which only the tumor cells expressed human CD47 12, 13, 14, 15. Considering this possibility, it will be important to see if sufficient levels of anti-CD47 antibodies can be achieved in the
One has to wonder whether SIRPα–CD47 blockade, in the presence of sufficient triggering of pro-phagocytic receptors, is enough to induce phagocytosis of all tumor cells. As a striking example against this idea, it was reported that several tumor cells failed to be phagocytosed in response to FcR-binding anti-CD47 antibodies [49]. Likewise, normal B cells were not phagocytosed in response to SIRPα–CD47 blockade, even though they expressed high levels of SLAMF7 [24]. Several possibilities may
Considering these observations, the therapeutic influence of SIRPα–CD47 blockade may be improved by relieving other constraints on phagocytosis. Obviously, this may be achieved by blocking additional inhibitory receptors or by stimulating other prophagocytic receptors on macrophages. It may also be done by modifying the properties of macrophages, through changes in the expression levels or functions of activating or inhibitory receptors, or alterations in other components of the phagocytic
Accumulating evidence suggests that blockade of the SIRPα–CD47 immune checkpoint is a promising new way to treat human cancer. Although there is already substantial knowledge regarding the SIRPα–CD47 checkpoint and the impact of its blockade, lessons learnt from other immune checkpoints indicate that a better mechanistic understanding of the SIRPα–CD47 pathway and its blockade will help to address key issues relevant for patient care in the future (see Outstanding Questions). First, this added
A.V. receives a contract from Bristol Myers-Squibb to study the mechanism of action of anti-SLAMF7 monoclonal antibody elotuzumab in multiple myeloma. This contract is unrelated to the topic described herein. A.V. holds the Canada Research Chair on Signaling in the Immune System. J.C. held a Fellowship from the Cole Foundation. The authors declare no conflict of interest. What is the importance of FcR engagement in the overall therapeutic efficacy of SIRPα–CD47 blockade? What are the relative
The authors thank members of their laboratory for useful discussions. Work in the authors’ laboratory was supported by grants from the Canadian Institutes of Health Research (MT-14429, MOP-82906, FDN-143338), Canadian Cancer Society Research Institute (Grant 018114) and the International Development Research Centre (Project #108403).