New PostAlpha-fetoprotein as a Shuttle for Medicines

Pregnancy is a natural phenomenon that ensures the survival of the species. The suppression of the immune response in pregnancy is robust since the embryo cells have half the father’s proteins that should be recognized by the mother’s immune system as foreign. Even surrogate motherhood is possible, with no genetic relationship to the embryo at all. The embryo cell is turning off a critical pathway required for the immune system to attack intruders. It secretes alpha-fetoprotein (AFP) that serves two critical functions: normalizes immune system responses so the mother’s immune cells don’t attack the embryo, and picks up nutrients from the mother and delivers them to the embryo. AFP induces downregulation of surface MHC class II antigens in their expression on human monocytes, thereby making embryonic cells “invisible” to the immune system. By reducing the antigen-presenting capacity of monocytes/macrophages, AFP functions as an essential factor in maintaining a fetal allograft as well as participating in the downregulation of the entire immune system in cancer [1]. AFP also supports the mother’s health in order to endure successful pregnancy and delivery. Symptoms of autoimmune diseases (ADs) are often less visible than before and after pregnancy. This correlates very well with the rise and fall of AFP [2].

MDSC as a magic target

Nature’s efficacy and safety in the wrong cell elimination cannot be beaten.

Monocytes/macrophages of the innate arm of the immune system are superior to T and B lymphocytes of the adaptive one for immune system response modulation. Myeloid-derived suppressor cells (MDSCs) are small heterogeneous cell populations of immature myeloid progenitors of granulocytes, macrophages, and dendritic cells (DCs) at different stages of differentiation generated from a common hematopoietic stem cell. They become immune cells that suppress, in particular, natural killer (NK) cells, which act as the first line of defense in the body. During pregnancy, MDSCs regulate many of the maternal-fetal tolerance mechanisms and could therefore be used to assist pregnant women to avoid miscarriages. MDSCs are the major immunity pacifiers in inflammation, injury, regeneration, transplantation, pathogenic infection, vaccination, etc. Beneficial effects of MDSC also include their lowering of blood glucose levels and reduction of insulin tolerance in obese individuals [3].

MDSCs are the major players in the tumor microenvironment (TME) that prevents cancer elimination. In individuals with cancer, MDSCs inhibit adaptive antitumor immunity by suppressing CD4+ and CD8+ T cell activation and function and by driving and recruiting T regulatory cells. They inhibit innate immunity by polarizing macrophages toward a type 2 tumor-promoting phenotype and by inhibiting NK-mediated cytotoxicity, while NK cells can destroy low-differentiated cancer stem cells (CSCs) and metastases [4]. CSCs are critical targets because of their potential to re-seed tumors; targeting them could eradicate the entire cancer. MDSC also promote cancer cell stemness, facilitate angiogenesis, and drive tumor invasion and metastasis. Because of their low presence in normal conditions and their prominent role in abnormal ones, including TME, they are known as “the most important cells you have never heard of” [5]. MDSCs account for approximately 30–50 percent of the tumor mass in glioma [6].

So, not cancer cells, but MDSC is the “magic target” for cancer treatment. MDSC prevents NK and cytotoxic T cells from executing cancer cells. MDSCs depletion unleashes the immune system to kill cancer [8].

MDSCs express the specific AFP receptor (AFPR) [9]. AFP transports ligands to AFP-binding MDSC and supports the immune system suppression (Fig. 1).