The latest review of nature | breakthrough of anti-cancer -- immunotherapy of CD47 antibody

In terms of mechanism, immunocheckpoint inhibitors, including CTLA-4 antibody, PD-1 antibody and PD-L1 antibody, act on the adaptive immune system, promote the activation of effector T cells by blocking the T cell inhibition pathway, and then enhance the anti-tumor immune responseIn recent years, scientists have been looking for ways to expand the number of people who benefit from immunotherapy because of the limited response rate of immunocheckpoint inhibitorsIn addition to developing well-known joint therapies based on immunosuppressive checkpoint inhibitors, such as combining different immunosuppressive checkpoint inhibitors, or combining immunosuppressive checkpoint inhibitors with T cell costimulatory molecules or other immunostimulatory receptor agonists (such as pembrolizumab combining 4-ibb agonist pf-05082566, nivolumab combining IL-15 hyperactivator alt-803), Some teams are also working on drugs that target another important branch of the immune system, the innate immune system< br / > innate immune system is the first non-specific defense line against infection and malignant cell transformationMonocytes, macrophages, dendritic cells and natural killer (NK) cells are all innate immune system cellsAmong them, the first three cells play the role of antigen presenting cells (APCs)The ability of APCs to engulf tumor cells through phagocytosis is an indispensable bridge between innate immunity and adaptive immunity< br / > Figure 1: regulation of tumor cell phagocytosis (picture source: Nature Reviews cancer) < br / > phagocytosis is a multi-step cell process, including target cell recognition, cell phagocytosis and lysosomal digestion, Regulated by receptor ligand (checkpoint) interactions between target cells and phagocytes, which play an important role in tumor cell immune monitoring (Figure 1)For healthy normal tissues and cells, they are born with the ability to express anti phagocytic molecules, so as to avoid being cleared by phagocytesHowever, cancer cells that cause headaches also learn a similar mechanism, and are more dependent on it than normal cellsHowever, based on the recognition of this way for cancer cells to evade immune attack, scientists believe that targeted phagocytic checkpoint (phagocytic checkpoint for short, such as cd47-sirp α) may provide a new way to develop cancer immunotherapy< br / > photo source: Nature Reviews cancer < br / > in a recent review published on Nature Reviews cancer on August 28 [1], six scientists from the United States city of Hope Comprehensive Cancer Center and other institutions introduced in detail the progress made in identifying phagocytic checkpoints in the past 20 years (Figure 2), And to support preclinical and early clinical evidence for the use of phagocytic checkpoint blockers in cancer treatmentAt the same time, we discussed the mechanism of regulating the innate and adaptive antitumor immune response after blocking the phagocytosis checkpoint, and emphasized how to bridge the two branches of the immune system is the key to produce the best anti-tumor immunity< br / > Figure 2: history of phagocytic checkpoint blocking development in cancer field (picture source: Nature Reviews cancer) < br / > 1Phagocytic checkpoint < br / > CD47 SIRP α axis is the first phagocytic checkpoint foundOther checkpoints involved in regulating phagocytic clearance and escape of tumor cells also include pd-1-pd-l1 axis and mhc-i-lilrb1 axis (Figure 1, figure 2)< br / > the CD47 SIRP α axis < br / > SIRP α is the first member of SIRP family It was identified in the late 1990s and expressed on myeloid cells, including all types of macrophages The interaction between CD47 and SIRP α was first found in 1999 [2] After a large number of studies confirmed that CD47 was widely expressed on the surface of normal cells By combining with SIRP α on the surface of macrophages, it released a "don't eat me" signal, so as to protect healthy cells from being "eaten" by macrophages Cancer cells have also learned this mechanism: overexpression of CD47 on the surface makes macrophages treat them as "normal cells", thus avoiding macrophage mediated phagocytic attack The < br / > pd-1-pd-l1 axis < br / > PD-1, also known as cd279, was first discovered in 1992 It belongs to the B7-CD28 superfamily and is induced to express in a variety of activated immune cells It is a marker of T cell depletion (dysfunction) At present, PD-1 has two known ligands, PD-L1 (also known as CD274 and B7-H1) and PD-L2 (also known as CD273 and B7-DC), which belong to the B7 family Although the pd-1-pd-l1 axis has traditionally been considered as a T cell (adaptive) immune checkpoint, a 2017 study showed that the pd-1-pd-l1 axis plays a new role in regulating the phagocytosis of tumor-related macrophages (TAMs), which is also a congenital immune checkpoint This study found that TAMs from early human and mouse tumors were similar to monocytes or macrophages from normal tissues (such as spleen and peripheral blood), which expressed the lowest level of PD-1, but with the growth of tumors, the expression of PD-1 in TAMs increased exponentially [3] In phenotype, most of PD-1 + TAMs are M2 like macrophages, which are the main macrophage group of mice and human colon cancer in the late stage [4], and their phagocytic ability to tumor cells is weaker than pd-1-tams The study also confirmed that disturbing pd-1-pd-l1 axis with PD-1 antibody or PD-L1 blocker can lead to antitumor response in mice lacking T cells, B cells and NK cells but still retaining functional macrophages In addition, knockout of PD-L1 expressed by tumor cells can significantly increase the phagocytosis of PD-1 + TAMs on tumor cells These findings strongly support the view that "PD-L1 expression on cancer cells can make them escape macrophage mediated phagocytosis" and that "blocking the pd-1-pd-l1 axis may induce both phagocyte and T cell-mediated antitumor immunity" < br / > mhc-i-lilrb1 axis < br / > in 2018, it has been reported that [5], the expression of MHC-I on cancer cells is related to their resistance to phagocytosis, and the underlying mechanism is that MHC-I and LILRB1 on macrophages play a role < br / > LILRB1, which belongs to the lilbr family, can be expressed in a wide range of tissues (such as monocytes, macrophages, eosinophils, basophils, dendritic cells, some NK cells, T cell subsets, B cells, etc.), especially in TAMs The above study also confirmed that [5], destroying mhc-i-lilrb1 interaction through gene manipulation can increase the susceptibility of cancer cells to phagocytosis in vivo and in vitro < br / > Second, phagocytic activation pathway < br / > in many cancers, the level of anti phagocytosis signal expressed by malignant cells is higher than that of normal cells, which may be to counter the increase of Pro phagocytosis signal expression (such as calreticulin, slamf7 and new tumor associated antigen) (Figure 1) < br / > calreticulin < br / > calreticulin, or calreticulin, has been shown to induce phagocytosis and downstream immune responses through a variety of mechanisms, which can be produced by target cells or macrophages to play these functions There is a large amount of evidence that calreticulin is the main phagocytic signal in tumors These studies emphasize the importance of calreticulin in clearing cancer cells by regulating innate immune system The < br / > slamf7 and Mac1 < br / > slam families consist of nine receptors, seven of which are expressed in macrophages, including CD48, T-lymphocyte surface antigen Ly-9, CD244, cd84, slamf7 (also known as cd319), slamf8 and slamf9 In cancer, slamf7 is believed to be a putative phagocytic signal that interacts with macrophage-1 antigen (Mac1, a heterodimeric complement receptor composed of integrins CD11b and CD18) expressed in many innate immune cells, including macrophages At present, further research is needed to elucidate the molecular mechanism of tumor cell phagocytosis mediated by slamf7 and identify other eat me signals that combine with slamf7 to induce phagocytosis The < br / > Fc receptor < br / > Fc receptor belongs to the cell surface receptor family It binds to the Fc domain of immunoglobulin and can activate downstream signaling pathways of various immune cell types (including macrophages, monocytes, dendritic cells, B cells, NK cells and granulocytes) Although traditionally known to play an anti-tumor role through antibody dependent cytotoxicity (ADCC), immunoglobulin G receptor (FC γ RS) also plays a major role in phagocytosis mediated antibody dependent cell phagocytosis In the human Fc γ r family, FC γ riib is the only phagocytic inhibitory receptor, while other members (FC γ RI, FC γ RIIA, FC γ RC, FC γ riiia, FC γ riiib) are phagocytic activated receptors It has been proved that targeting phagocytic activated receptors such as FC γ RS with therapeutic antibodies (such as CD20 antibody obinutuzumab [6]) is a reasonable way to combine phagocytic checkpoint block to promote phagocytic clearance of tumor cells < br / > 3 Bridging innate immunity and adaptive immunity < br / > generating antigen-specific T-cell response < br / > although the initial anti-tumor effect of blocking phagocytic checkpoint with CD47 antibody is largely due to the direct elimination of tumor cells by phagocytes, more and more evidences show that adaptive immune system, In particular, CD8 + T cell response plays an important role in the anti-tumor effect of CD47 antibody (Figure 3) For example, in 2015, a study published in nature medicine [7] confirmed that CD47 blockade triggered T-cell-mediated immunogenic tumor destruction In 2016, a study published on PNAs [8] confirmed that adaptive immune stimulation is required for CD47 to block long-term anti-tumor response: in the mouse model of B16F10 melanoma, antibodies targeting CD47 and mouse melanoma antigen tyrosinase-1 (TRP-1) cooperate with PD-L1 antibody to produce long-term anti-tumor response, This is not achieved by single drug therapy with CD47 antibody or combined with TRP-1 antibody < br / > Figure 3 bridging innate and adaptive anti-tumor immunity (picture source: Nature Reviews cancer) < br / > cgas-sting pathway < br / > the above paper published on Nature Medicine [7] also confirmed that the T-cell activation and anti-tumor effect blocked by CD47 seems to depend on the activation of cgas-sting signal in antigen presenting cells (such as dendritic cells) Specifically, in wild-type (not lacking sting) mice carrying homologous MC38 tumors, the use of CD47 antibody treatment increased the production of type I interferon and led to an anti-tumor response However, compared with dendritic cells from wild-type mice, the ability of dendritic cells isolated from mice lacking sting to activate CD8 + T cells when cultured with tumor cells and treated with CD47 antibody was reduced These results indicate that the activation of cgas-sting pathway in host cells is essential for interferon production and anti-tumor adaptive immunity at least when CD47 is blocked < br / > Figure 4 phagocytosis and innate immune response pathway activation (picture source: Nature Reviews cancer) < br / > TLR pathway < br / > cells of innate immune system depend on pattern recognition receptors (PRRS) encoded by germ cells and other cell surface receptors to detect membrane molecules on microbial proteins or tumor cells rapidly As the most characteristic PRRs, Toll like receptors (Toll-like receptors, TLRs) can detect damage-associated molecular patterns (DAMPs) released into the tumor microenvironment or tumor related DAMPs released by cancer cells in phagocytosis, thus leading to activation of downstream inflammatory pathways (Fig 4) A review published as early as 2008 has concluded that TLR activation is essential for key immune processes, including antigen processing and cross presentation, costimulatory molecules (including