CAR-macrophage: Powerful Immune Enhancer to Fight Cancer
Posted: Oct 09, 2022
Macrophages are common phagocytes in various mammalian tissues, which play many different roles in normal development, homeostasis, tissue repair and even immune response to pathogens. Their diversity means that they are involved in almost every human disease, and are also the main therapeutic target because their functions can be enhanced or inhibited to change the circumstances of the disease.
- What are macrophages?
In the word macrophage, "macro" means "huge" and "phage" refers to phagocytes. Phagocytes are some cells with phagocytic function in the body, such as monocytes, granulocytes, etc. Among them, macrophage plays an important role in the process of the immune system to clear foreign antigens.
The main function of macrophages is to phagocytose cell fragments and pathogens in body fluids and tissues, and activate lymphocytes or other immune cells through antigen presentation function to make them respond to pathogens. There are three main sources of macrophages: precursor cells in the embryo, hematopoietic stem, and monocytes. Macrophages develop in different tissues and organs, and transfer to damaged or diseased tissues to perform functions such as tissue repair and inflammation.
Modern research shows that macrophages also play a very important role in the occurrence and development of tumors. There are a large number of macrophages in solid tumors, which we call TAM (Tumor-Associated Macrophage). Tumor tissue is very complex. In addition to tumor cells, there are extracellular matrix proteins, cancer stem cells, cancer associated fibroblasts (CAFs), blood vessels, etc. Together with the cytokines secreted by these cells and various extracellular substances, they form a complex environment, the tumor microenvironment (TME)
- Macrophages as a double-edged sword in tumor development
Cells in the tumor microenvironment interact with each other, providing an indispensable condition for the growth and metastasis of tumor cells. Similarly, the macrophages that persist in the tumor microenvironment are not spared, so some of them become rebels in the TME. This is the infamous M2-type macrophages. Those that still adhere to the heroic are called M1-type macrophages. After being countered, M2 type begin to exert immunosuppressive functions (such as secreting IL-10, TGF-β and other cytokines), and can promote angiogenesis to provide nutrients for tumor cells.
M2-type macrophages are harmful. So, in the process of tumor treatment, some methods might be adopted to enhance the activity of macrophages, so as to avoid the transformation of TAM into M2 type, and at the same time, to enhance the killing of tumors by M1 type.
- Transformation of macrophages—CAR-M
In June 2018, Dr. Saar Gill and Dr. Michael Klichinsky, CAR-T cell therapy experts from the University of Pennsylvania, began to work on CAR-macrophage therapy development to treat tumors.
In their published article, Klichinsky used CAR targeting HER2 to modify macrophages, with a mouse model to evaluate the tumor-killing effect of CAR-macrophage (CAR-M) cells. In the SKOV3 human ovarian cancer mouse model, it can be seen that CAR-M can effectively kill tumors and prolong the overall survival of mice, and can also reduce the lung metastasis of SKOV3 cells.
"In addition to killing tumor cells, scientists also discovered a more important function of CAR-M, that is, to resist TAM to transform into M20-type macrophages and make TAM actively transform into M1 type. In addition, even some cells have already transformed into M2 type, expression of the CAR structure can reverse the transformation of these cells into M1 type." introduced by a scientist at Creative Biolabs, a biotech company focusing on CAR-T and CAR-M therapy development services.
The research has proved that CAR-M successfully resisted the influence of TAM in the mouse model and transformed into M1-type macrophages, thus exerting a tumor-killing function. It’s believed that with the further development of science and technology, CAR-M technology will soon start clinical trials and show its effects on patients.
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