Six scientists from the U.S. City of Hope Comprehensive Cancer Center and others detailed the progress made in identifying phagocytosis checkpoints over the past 20 years and the clinical support for the use of phagocytosis checkpoint blockage in cancer treatment Pre and early clinical evidence.



Phagocytosis checkpoint



The CD47-SIRPα axis is the first tumor phagocytosis checkpoint to be discovered. Other checkpoints involved in regulating tumor cell phagocytosis clearance and escape include the PD-1-PD-L1 axis and the MHC-I-LILRB1 axis.



CD47-SIRPα axis



SIRPα, called signal-regulatory protein α, is the first member of the SIRP family. It was identified in the late 1990s and expressed on myeloid cells, including all types of macrophages. The interaction between cd47 antibody and SIRPα was first discovered in 1999, and a large number of studies have confirmed that CD47 is widely expressed on the surface of normal cells. By binding to SIRPα on the surface of macrophages, it releases a signal of "don't eat me" This protects healthy cells from being "eaten" by macrophages. Cancer cells have also learned this mechanism: CD47 is overexpressed on the surface, causing macrophages to treat them as "normal cells," thereby evading macrophage-mediated phagocytic attacks.



Bridging innate and adaptive immunity



Antigen specific T cell response



Although the initial antitumor effect of checkpoints using CD47 to block phagocytosis was largely due to the direct clearance of tumor cells by phagocytes, there is growing evidence that the adaptive immune system, especially CD8 + T The cellular response also plays a crucial role in the antitumor effect of CD47 antibodies (Figure 3). For example, in 2015, a study published in Nature Medicine confirmed that CD47 blockade triggered T cell-mediated immunogenic tumor destruction. In 2016, a study published on PNAS confirmed that CD47 blocks adaptive antitumor response by adaptive immune stimulation: targeting CD47 and mouse melanoma antigens in a homologous B16F10 melanoma mouse model The tyrosinase-associated protein 1 (TRP-1) antibody works in synergy with PD-L1 antibody to produce a durable antitumor response, which cannot be achieved with anti cd47 antibody monotherapy or combined with TRP-1 antibody.



Targeted phagocytosis checkpoint



The CD47-SIRPα axis is the most thorough checkpoint for phagocytosis that has been studied in the cancer field. Therapies that target the CD47-SIRPα axis are now being investigated clinically for the treatment of a variety of human cancers (Table 1). Studies have shown that blocking the CD47-SIRPα interaction can lead to phagocytosis against cancer cells, and this blocking can be achieved in a variety of ways, including 1) using CD47 or SI47 targeting SI47 binding sites to block their interaction or SIRPα antibody; 2) the use of recombinant protein composed of CD47 or SIRPα extracellular region (the role is to compete with endogenous proteins, affect the normal binding of CD47 and SIRPα); 3) use targeted regulation CD47 transcription and / or transport pathway drugs to inhibit the expression of CD47 on the surface of cancer cells.



At present, phagocytosis checkpoint blocking, especially the treatment of CD47-SIRPα axis, has proven to be a promising therapy in both hematological and solid malignancies, with acceptable safety and toxicity characteristics. . Next, larger clinical studies and longer follow-up periods are needed to validate current findings. Whether targeting other phagocytosis checkpoints can produce similar therapeutic benefits remains to be seen.