Fooled macrophages
A few words about how malignant tumors deceive the immune system
In addition, the immune system is able to effectively recognize and destroy transformed own cells that can degenerate into malignant tumors. However, failures in the immune system (for genetic or other reasons) lead to the fact that once malignant cells take over. The overgrown tumor becomes insensitive to the attacks of the body and not only successfully avoids destruction, but also actively "reprograms" protective cells to meet its own needs. By understanding the mechanisms that the tumor uses to suppress the immune response, we will be able to develop countermeasures and try to shift the balance towards activating the body's own defenses to fight the disease.
Tumor and immunity – a dramatic dialogue in three parts with a prologueFor a long time it was believed that the reason for the low effectiveness of the immune response in cancer is that tumor cells are too similar to normal, healthy ones for the immune system, tuned to search for "strangers", to be able to properly recognize them.
This explains the fact that the immune system most successfully resists tumors of a viral nature (their frequency increases sharply in people suffering from immunodeficiency). However, it later became clear that this was not the only reason.
It turned out that the interaction of cancer cells with the immune system is much more versatile. The tumor does not just "hide" from attacks, it is able to actively suppress the local immune response and reprogram immune cells, forcing them to serve their own malignant needs.
The "dialogue" between the reborn, out-of–control cell with its offspring (that is, the future tumor) and the body develops in several stages, and if at first the initiative is almost entirely on the side of the body's defenses, then at the end (in case of disease development) it goes to the side of the tumor. A few years ago, oncoimmunologists formulated the concept of "immunoediting", describing the main stages of this process (Fig. 1) [2].
Figure 1. Immunoediting during the development of a malignant tumor.
The first stage of immunoredaction is the elimination process. Under the influence of external carcinogenic factors or as a result of mutations, a normal cell "transforms" – acquires the ability to divide indefinitely and not respond to regulatory signals of the body. But at the same time, as a rule, it begins to synthesize special "tumor antigens" and "danger signals" on its surface. These signals attract cells of the immune system, primarily macrophages, natural killers and T cells. In most cases, they successfully destroy the "spoiled" cells, interrupting the development of the tumor. However, sometimes among such "precancerous" cells there are several in which immunoreactivity – the ability to cause an immune response – is weakened for some reason, they synthesize fewer tumor antigens, are less recognized by the immune system and, having survived the first wave of the immune response, continue to divide.
In this case, the interaction of the tumor with the body enters the second stage, the equilibrium stage. Here, the immune system can no longer completely destroy the tumor, but it is still able to effectively limit its growth. In such an "equilibrium" (and undetectable by conventional diagnostic methods) state, micro-tumors can exist in the body for years. However, such hidden tumors are not static – the properties of their constituent cells gradually change under the influence of mutations and subsequent selection: the advantage among dividing tumor cells is obtained by those who are better able to resist the immune system, and eventually immunosuppressive cells appear in the tumor. They are able not only to passively avoid destruction, but also to actively suppress the immune response. In fact, this is an evolutionary process in which the body unwittingly "brings out" exactly the type of cancer that will kill it.
This dramatic moment marks the transition of the tumor to the third stage of development – escape, at which the tumor is already insensitive to the activity of cells of the immune system, moreover, it turns their activity to its advantage. It begins to grow and metastasize. It is such a tumor that is usually diagnosed by doctors and studied by scientists – the two previous stages are hidden, and our ideas about them are based mainly on the interpretation of a number of indirect data.
Dualism of the immune response and its significance in carcinogenesisThere are many scientific articles describing how the immune system fights tumor cells, but no fewer publications demonstrate that the presence of immune system cells in the immediate tumor environment is a negative factor correlating with accelerated growth and metastasis of cancer [2, 3].
Within the framework of the concept of immunorediting, which describes how the nature of the immune response changes as the tumor develops, such ambivalent behavior of our defenders has finally received its explanation.
The reorientation of the immune system from the fight against the tumor to its protection is possible due to the plasticity of the cells of this system. Speaking about the immune response, we usually use "militant" metaphors – "struggle", "destruction", "suppression". But it is not enough to destroy the enemy, be it a virus, a bacterium or another parasite. The body must also correct the damage caused by it. Regeneration of damaged tissues and wound healing are also under the control of immune system cells: she is not only a "warrior", but also a "healer". The insidiousness of cancer lies in the fact that, being essentially a "foreign agent" in the body, it secretes special substances that suppress the active immune response and encourage white blood cells to perceive the tumor not as an enemy requiring destruction, but as a wound requiring help, protection and healing.
We will look at some of the mechanisms of how this happens, using the example of macrophages. The tumor uses similar techniques to deceive other cells of innate and acquired immunity.
Macrophages – "warrior cells" and "healer cells"Macrophages are perhaps the most famous cells of innate immunity – it was with the study of their abilities for phagocytosis by the Mechnikov that classical cellular immunology began.
In the mammalian body, macrophages are the vanguard of combat: when they are the first to detect an enemy, they not only try to destroy it on their own, but also attract other cells of the immune system to the place of battle, activating them. And after the destruction of foreign agents, they are actively involved in the elimination of the damage caused, developing factors that contribute to wound healing. Tumors use this dual nature of macrophages to their advantage.
Depending on the predominant activity, two groups of macrophages are distinguished: M1 and M2. M1-macrophages (they are also called classically activated macrophages) – "warriors" – are responsible for the destruction of foreign agents (including tumor cells), both directly and by attracting and activating other cells of the immune system (for example, T-killers). M2 macrophages – "healers" – accelerate tissue regeneration and ensure wound healing [4, 8].
The presence of a large number of M1 macrophages in the tumor inhibits its growth [5], and in some cases can even cause almost complete remission (destruction). And vice versa: M2 macrophages secrete growth factor molecules that additionally stimulate the division of tumor cells, that is, they favor the development of malignant formation. Experimentally, it was shown that M2 cells ("healers") usually predominate in the tumor environment. Worse: under the action of substances secreted by tumor cells, active M1 macrophages are "reprogrammed" into M2-type [6], cease to synthesize anti-tumor cytokines such as interleukin-12 (IL12) or tumor necrosis factor (TNF) and begin to release molecules into the environment that accelerate tumor growth and the germination of blood vessels vessels that will provide its nutrition, for example, tumor growth factor (TGFb) and vascular growth factor (VGF). They cease to attract and initiate other cells of the immune system and begin to block the local (antitumor) immune response (Fig. 2).
Figure 2. M1- and M2-macrophages: their interaction with the tumor and other cells of the immune system.
Proteins of the NF-kB family play a key role in this reprogramming [7]. These proteins are transcription factors that control the activity of many genes necessary for M1 activation of macrophages. The most important representatives of this family are p65 and p50, which together form the p65/p50 heterodimer, which in macrophages activates many genes associated with an acute inflammatory response, such as TNF, many interleukins, chemokines and cytokines. The expression of these genes attracts more and more immune cells, "highlighting" the area of inflammation for them. At the same time, another homodimer of the NF family -kB – p50/p50 – has the opposite activity: by binding to the same promoters, it blocks their expression, reducing the degree of inflammation.
Both the activity of NF-kB transcription factors is very important, but the balance between them is even more important. It has been shown that tumors purposefully secrete substances that disrupt the synthesis of p65 protein in macrophages and stimulate the accumulation of the p50/p50 inhibitory complex [7]. In this way (in addition to a number of others), the tumor turns aggressive M1 macrophages into unwitting accomplices of its own development: M2-type macrophages, perceiving the tumor as a damaged area of tissue, include a recovery program, but the growth factors secreted by them only add resources for tumor growth. This closes the cycle – the growing tumor attracts new macrophages, which are reprogrammed and stimulate its growth instead of destruction.
Reactivation of the immune response is an actual direction of anticancer therapy
Thus, in the immediate environment of tumors there is a complex mixture of molecules: both activating and inhibiting the immune response. The prospects for the development of the tumor (and therefore the prospects for the survival of the organism) depend on the balance of the ingredients of this "cocktail". If immunoactivators prevail, it means that the tumor has not coped with the task and will be destroyed or its growth will be greatly slowed down. If immunosuppressive molecules prevail, it means that the tumor was able to pick up the key and will begin to progress rapidly. By understanding the mechanisms that allow tumors to suppress our immunity, we will be able to develop countermeasures and shift the balance towards the destruction of tumors [8].
Experiments show that the "reprogramming" of macrophages (and other cells of the immune system) is reversible. Therefore, one of the promising areas of oncoimmunology today is the idea of "reactivating" the patient's own immune system cells in order to enhance the effectiveness of other treatment methods. For some types of tumors (for example, melanomas) this allows you to achieve impressive results. Another example discovered by Medzhitov's group [9] is ordinary lactate, a molecule that is produced with a lack of oxygen in fast–growing tumors due to the Warburg effect [10]. This simple molecule stimulates the reprogramming of macrophages, forcing them to support tumor growth. Lactate is transported inside macrophages through membrane channels, and a potential therapy is to block these channels.
The development of anti—cancer therapy methods is currently going in several directions at once (biomarkers [11] and bioinformatic analysis [12] are just some of these methods. — Ed.), and they are all important. After all, having learned to manage the immune response as effectively as malignant tumors do, we will be able to finally "beat" this disease, which remains one of the main causes of mortality in Russia and in the world.
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