Physiological organization of immune response based on the homeostatic mechanism of matrix reprogramming: Implication in tumor and biotechnology

Abstract

It is accepted that the immune system responds to pathogens with activation of antigen-independent innate and antigen-dependent adaptive immunity. However many immune events do not fit or are even inconsistent with this notion. We developed a new homeostatic model of the immune response. This model consists of four units: a sensor, a regulator, an effector and a rehabilitator. The sensor, macrophages or lymphocytes, recognize pathogenic cells and generate alarm signals. The regulator, antigen-presenting cells, Тregs and myeloid-derived suppressor cells, evaluate the signals and together with sensor cells program the effector. The effector, programmed macrophages and lymphocytes, eliminate the pathogenic cells. The rehabilitator, M2 macrophages, restrict inflammation, provide angiogenesis and reparation of tissue damage, and restore the homeostasis. We suggest the terms "immune matrix" for a biological template of immune responses to pathogens and "matrix reprogramming" for the interdependent reprogramming of different cells in the matrix. In an adequate immune response, the matrix forms a negative feedback mechanism to support the homeostasis. We defined the cellular and phenotypic composition of a tumor immune matrix. A tumor reprograms the homeostatic negative feedback mechanism of matrix into a pathogenic positive feedback mechanism. M2 macrophages play a key role in this transformation. Therefore, macrophages are an attractive target for biotechnology. Based on our hypotheses, we are developing a cell biotechnology method for creation of macrophages with a stable antitumor phenotype. We have shown that such macrophages almost doubled the survival time of mice with tumor.

Current Concept and Update of the Macrophage Plasticity Concept: Intracellular Mechanisms of Reprogramming and M3 Macrophage “Switch” Phenotype

“…Among them are the following: (1) immune factors, such as immune complexes and cytokines [ 25 ]; (2) pathogen-associated molecular patterns (PAMP), such as LPS, microbial nucleic acids, proteins, or carbohydrates that can be recognized by PRR of macrophages; (3) physical and chemical factors, such as hypoxia [ 26 ], fever, and pH [ 27 ]. It has recently been proposed that factors which shift macrophage phenotype towards M1 be referred to as reprogramming factor- (RF-) M1 and those which shift the phenotype towards M2 as RF-M2 [ 28 ]. For instance, RF-M1 is used for IFN- γ and low concentrations of serum [ 29 ], and RF-M2 is used for IL-4 and high concentrations of serum [ 14 ].…”

Reprogramming macrophages toward M1-like phenotypes in the breast cancer microenvironment using mesenchymal stromal/stem cells: A review

“…Reprogramming is better suited to explain the formation of any cell phenotype since it would be more appropriate to consider that the M1-like phenotype has more M1 markers than M2 markers and vice versa 87 . Normally, macrophages can be reprogrammed either to the M1-like or M2-like phenotype based on the type of pathogen detected to provide a rapid and appropriate immune response 90 . Therefore, the concept of investigating macrophage plasticity by reprogramming the TAM phenotype into an M1-like phenotype is emerging as a plausible therapeutic method for cancer treatment.…”

M3 Macrophages Stop Division of Tumor Cells In Vitro and Extend Survival of Mice with Ehrlich Ascites Carcinoma

“…We have hypothesized that tumor growth can be effectively restricted by a special switch phenotype [ 19 ]. The switch phenotype, in contrast to the M1 phenotype, should respond to anti-inflammatory pro-tumor cytokines by increasing production of pro-inflammatory anti-tumor cytokines.…”