preface

Car-t cell therapy is a kind of cellular immunotherapy. It refers to the method of transferring genetic material with specific antigen recognition domain and T cell activation signal to T cells by gene cloning technology, so that T cells can be directly activated by combining with specific antigen on the surface of tumor cells. Car-t cells have been successfully used in the treatment of circulatory malignancies, such as B-cell-derived malignancies. After the success of car-t therapy, people applied car strategy to NK cells and developed car-nk cell therapy similar to car-t therapy.

The two main cell types of monocyte phagocytic system (MPS) are monocytes and monocyte derived macrophages, which have phagocytic function. MPs selectively engulfs external targets such as microorganisms. However, macrophages are unable to recognize and attack tumors. Even in tumor tissues, macrophages do not play a role in phagocytosis or antigen presentation. Instead, they turn into immunosuppressive M2 type, which prevents the immune system from clearing tumor cells.

In addition, in addition to the positive signal of macrophage phagocytosis, the opposite signal prevents macrophages from phagocytizing target tumor cells, such as CD47. These signals have become a hot research field since they were discovered.

In view of the success of car-t cell therapy and the development potential of car-nk cells, researchers are interested in developing car macrophages (car-m) for tumor immunotherapy. The emergence of car-m opens up a new possibility for the treatment of solid tumors: to modify human macrophages with specific cars to improve their phagocytic activity and antigen presentation.

Research progress of car-m

At present, many attempts have been made to treat cancer with car-m. Researchers have designed chimeric antigen receptor phagocytes (car-p), which can guide macrophages to phagocytize specific target cells.

It has been proved that car-p expressing the intracellular domain of megf10 or fcrv can promote the phagocytosis of target antigen. Car-pmegf10 can specifically trigger the phagocytosis of targeted ligands, and initiate the phagocytosis through the local signal cascade of tyrosine phosphorylation, tcr-cd3 ζ The phagocytosis of car-p may be promoted by the recruitment of Syk kinase.

Whole cell phagocytosis is rare, but gnawing target cells is more frequent, which indicates that the interaction between car-p macrophages and target cells is not enough to trigger direct whole cell phagocytosis. Previous studies have found that PI3K Signal plays an important role in the endocytosis of large targets, which can promote the phagocytosis of macrophages. The researchers linked the p85 subunit of PI3K with car-p-fcrv to form a car tandem. Car ptandem has good whole cell phagocytosis.

Researchers at the University of Pennsylvania use CD3 - ζ Car-m of HER2 in the intracellular domain. In two models of heterotopic mice transplanted with solid tumor, single injection of HER2 car M can reduce the tumor load and prolong the survival time of mice. In the human-induced mouse model, HER2 car M can transform M2 macrophages into M1 macrophages, induce inflammatory tumor microenvironment and enhance the anti-tumor cytotoxicity of T cells. In addition, it is found that HER2 car m may produce epitope diffusion, which provides a new way to avoid tumor immune escape.

Zhang et al. Used induced pluripotent stem cells (iPSCs) to express car structure and differentiate into macrophages, named car IMAC. The results showed that the iPSCs expressing car could differentiate into macrophage like cells. In the absence of antigen, car IMAC was closer to M2 polarization. However, in the presence of specific antigens, such as CD19, car mediated signaling promotes the phagocytosis of car IMAC and leads to the transformation of car IMAC into pro-inflammatory M1. IPSC derived macrophages may be an important cell source for immunotherapy of myeloid tumors.

One of the important reasons for the failure of car-t in the treatment of solid tumors is that T cells are difficult to enter the tumor tissue. This is because the physical barrier formed by extracellular matrix (ECM) of solid tumor prevents T cells from entering tumor tissue. ECM is produced by highly ordered fibrous molecules, glycoproteins and other macromolecules. Its synthesis and degradation are mainly regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Macrophages are an important source of MMP.