Immune matrix and its abnormal reprogramming by tumor
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1
Moscow State University of Medicine and Dentistry n.a. A.I.Evdokimov, Russia
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2
Institute of General Pathology and Pathophysiology, Russia
INTRODUCTION: The rapid reaction of the immunity to pathogens is due to the fact that immune mechanisms are reproduced from a ready-made physiological matrix. We called this template of immune mechanisms activated in response to pathogens, an immune matrix. Matrix contains points with various immune cells. During the response, immune cells can change their phenotype. For example, macrophages may have a proinflammatory M1 or the anti-inflammatory M2 phenotype [1, 2]. The process of changing cell phenotype is called “reprogramming” [3]. For interdependent reprogramming of different immune cells of the matrix, we propose the term “matrix reprogramming”. The idea of immune matrix helps better understand the immune system performance and pathogenesis of immune disorder in various diseases. Here, we analyze an normal matrix reprogramming and its disorder induced by tumor. Macrophages have a crucial role in the protumor transformation of immune matrix. We try to develop a in vitro biotechnology for the creation of macrophages with a stable antitumor M1 phenotype.
1. IMMUNE MATRIX AND ANTITUMOR DEFENSE
The immune system responds to pathogens with the successive launch of innate and adaptive immune responses. The activation of macrophages, natural killer (NK) cells, neutrophils, basophils and eosinophils to pathogens is the onset of an innate immunity and the start of macrophage programming. The phenotype formed under the action of intracellular microbes and/or IFN-γ is termed M1, and the phenotype formed by the action of extracellular parasites and/or IL-4 and IL-13 is termed M2 [4]. Then macrophages, NK cells and antigen-presenting cells (APCs) launch the adaptive immunity. During the innate and adaptive responses occurs the successive reprogramming of immune cells: macrophages to an M1 or M2 phenotype, which subsequently reprograms Тh0 cells to a Th1 or Th2 phenotype and T cells to a cytotoxic T lymphocyte (CTL) phenotype. Following the reprogramming of Th and CTL cells by macrophages, they programs macrophages. We propose this process of mutual reprogramming of immune matrix cells be called “matrix reciprocal reprogramming.” Matrix reciprocal reprogramming provides a rapid and effective type of immune response, either the pro- or anti-inflammatory, Th1 cellular or Th2 humoral response, required for effective elimination of pathogen.
T regulatory cells (Tregs) regulate all steps of immune responses as follows: 1) activity of macrophages and NK cells and, thereby, the innate response; 2) antigen presentation and, thereby, the launch of adaptive responses; and 3) Th, В and Т cells and, thereby, the adaptive response itself. Myeloid-Derived Suppressor Cells (MDSCs) also control the immune responses [5]. MDSCs are activated by inflammatory cytokines suggesting that in normal immune response, MDSCs prevent excessive inflammation and immune responses. Therefore, pathogen-specific, Treg- and MDSC-controlled matrix reciprocal reprogramming of immune cells provides the plasticity of the immune response, that is, a capability of the immune response to rapidly alter its direction of development.
The physiological end-point of the immune matrix is the restoration of homeostasis disturbed by pathogenic cells. Homeostasis is maintained by negative feedback mechanisms consisting of a sensor, a regulator and an effector. The architecture of the immune matrix clearly demonstrates the homeostatic mechanisms within the matrix. The sensor is macrophages, which recognize pathogenic cells and generate warning signals of disturbed homeostasis. The regulator is APCs, Тregs and MDSCs. APCs “evaluate” the antigen and then program Th cells to effector Th1 or Th2 and T cells to CTLs. The programmed effector cells eliminate the pathogenic factor and restore homeostasis.
One of the important aims of the homeostatic mechanism of the matrix is to destroy tumor cells and to fix homeostasis disturbed by tumor. The antitumor immune events includes: 1) tumor-associated macrophage (TAM) programming to an М1 phenotype; 2) activation of the innate response evident as antitumor effects of ТАМ-М1 and NK cell activation; 3) presentation of the tumor antigen and release of programming cytokines by ТАМ-M1, APCs and NK; 4) activation of the adaptive response evident as programming of Th1 and CTL cells; and 5) Th1- and CTL-dependent restriction of tumor growth. Together, all these events reflect the antitumor matrix reprogramming of immune cells. Disorders at any step of this matrix reprogramming results in the failure of the immune system to eliminate tumor cells and to restore disturbed homeostasis. One outcome of this is the increased chance for the onset of aggressive tumor disease.
2. ABNORMAL IMMUNE MATRIX REPROGRAMMING AND TUMOR PATHOGENESIS
Disturbed sensor units (macrophages) and tumor growth. The tumor itself attracts macrophages designed for tumor destruction and then reprograms the antitumor M1 macrophage phenotype to a protumor M2 phenotype by secreting IL-4, IL-10 and TGF-β [6]. Reprogrammed ТАМ-М2 perform various protumor functions [7]: 1) promote the division and survival of tumor cells; 2) promote degradation of the basement membrane and facilitate the migration of tumor cells; 3) stimulate angiogenesis; and 4) promote metastasis.
Disturbed regulatory unit (Tregs and MDSCs) and tumor growth. The tumor can also reprogram the regulatory unit of this matrix, Tregs [8] and MDSCs, which can promote tumor growth. The tumor abnormally reprograms Tregs using four molecular and cellular instruments: 1) chemokine to attract Tregs; 2) TGF-β to activate the attracted Tregs; 3) expression of normal antigens that stimulates Treg suppressor activity; and 4) tumor-specific Tregs that suppress the antitumor immune response. The abnormal reprogramming of Tregs and MDSCs (regulator) by the tumor inevitably affects the capability of macrophages (sensor), Th1s and СТLs (effector) to perform their antitumor functions [5; 9].
Disturbed effector unit (CTLs) and tumor growth. CTLs are the most effective at killing tumor cells. However, in the tumor microenvironment, CTLs release cytotoxic granules at a slower rate [10]. As a result, the tumor continues to grow despite the cytotoxic effect of CTLs. The decrease in CTL antitumor activity is due to the effect of tumor-reprogrammed ТАМ-2s, Tregs and MDSCs [11, 12].
Thus, the tumor inverts the sensor responses of TAMs, disturbs the regulatory functions of APCs, MDSCs and Tregs, prevents maturation of effector CTLs and Th1 cells, and does not allow formation of the homeostatic mechanism of the immune matrix. The loss of matrix ability to restore homeostasis plays a key role in tumor growth.
Immune matrix abnormally reprogrammed by tumors do not provide homeostasis. The tumor can affect any component of the matrix homeostatic mechanism including the sensor (macrophages), the regulator (APCs, Тregs and MDSCs) and the effector (Th1 and СTL cells). Furthermore, tumor intervention of the immune matrix does not merely suppress parts of the homeostatic mechanism, but transforms the homeostatic mechanism into a protumor program. As a result, the immune matrix fails to restore homeostasis disturbed by tumor growth.
3. THE CREATION OF IMMUNE CELLS RESISTANT TO TUMOR REPROGRAMMING
The concept of matrix reprogramming provides new insights into tumor pathogenesis and possibilities for treatment of oncologic diseases. A considerable break-through in immune suppression of carcinogenesis may be possible after solving the problem of prevention of protumor reprogramming of immune cells and restoration of antitumor matrix reprogramming. We recently started development of cell biotechnology focused on solving the problem. Based on the key trigger, the protumor role of the abnormally reprogrammed M2 macrophages, we wanted to develop the in vitro method for reprogramming of macrophages to a stable antitumor M1 phenotype. Such reprogrammed macrophages administered back to the tumor could possibly restrict tumor growth and delay disruption of the homeostatic mechanism of the immune matrix. We have shown that administration of reprogrammed M1 macrophages to mice with Erlich’s tumor doubled their survival time.
Acknowledgements
The study was supported by grant 16.740.11.0007 as a part of Targeted Federal Program “Scientific and Academic Specialists for Innovations in Russia”, 2009-2013
References
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Keywords:
Immunity,
tumor,
macrophage,
reprogramming,
immune matrix
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune-mediated disease pathogenesis
Citation:
Malyshev
I,
Kalish
S and
Manukhina
E
(2013). Immune matrix and its abnormal reprogramming by tumor.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00459
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Received:
30 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Prof. Igor Malyshev, Moscow State University of Medicine and Dentistry n.a. A.I.Evdokimov, Moscow, Russia, iymalyshev1@gmail.com