The study of antitumor immunity and the elimination of the factors causing its deterioration are important problems in modern medicine. Malignant neoplasms occupy one of the leading places among the causes of mortality and disability in developed countries. Normally, the balance of the number of dividing and dying cells is naturally regulated. If cell multiplication becomes uncontrolled, then malignant tumors occur. The mechanism of control of this process by the immune system depends on several factors that suppress or stimulate the process of excessive division.
general description
Immunity is understood to mean the totality of the protective mechanisms of a living organism from the negative effects of foreign agents. Most often, these processes are associated with infectious (bacterial, viral, fungal, protozoal) diseases. However, there are other methods of protection, one of which is antitumor immunity.
In the activity of any living organism, moments arise when it needs rapid cell division (trauma, inflammation, and others). With the development of a specific immune response, the number of cells sensitive to the effects of antigen (a molecule associated with an antibody) increases by several thousand times. In the normal course of the process, after completion of this reaction, accelerated cell division stops.
A malignant tumor is characterized by a violation of this mechanism. Cell reproduction continues continuously and is independent. Gradually, normal tissues in the affected organ are replaced and the tumor grows into the surrounding areas. Moving along the bloodstream, the tumor cells continue to divide in another location, which leads to the appearance of metastases. This defect of continuous division is inherited by all descendants of tumor cells. Their membranes are changed in such a way that the human body perceives objects as alien.
On the other hand, there is a way in the body that can stop this process - antitumor immunity. In immunology, the onset of tumors is evidence of a violation of the natural defense mechanism.
Discovery story
As early as the 18th century, it was noticed that in some patients who underwent infectious diseases, malignant tumors disappeared. At the end of the 19th century, an American oncologist surgeon, William Coley, revealed a relationship between infection of hemolytic streptococcus Streptococcus pyogenes and a decrease (and in some cases a complete disappearance) of malignant tumors. He developed an anti-cancer vaccine based on these bacteria to treat patients with sarcoma. At that time, the mechanisms of antitumor immunity in immunology were not yet known, so his work was subjected to strong criticism, and subsequently was forgotten for almost 100 years.
In the middle of the 20th century, it was discovered that the introduction of the liposaccharide macromolecules, which make up the shells of microbial cells, can lead to the death of tumors. However, in the 70s. XX century scientists found that this process does not cause liposaccharide itself, but a protein factor (tumor necrosis factor, or TNF), produced by the following types of cells of the immune system in contact with microbes:
- activated macrophages;
- neutrophils;
- T lymphocytes
- mast cells;
- astrocytes;
- NK cells (natural killers).
The relationship of immunity and tumor formation
The following facts testify in favor of the presence of a relationship between the state of immunity and the development of malignant tumors:
- the increased prevalence of such neoplasms in patients with immunodeficiency, as well as in old age (which is associated with a decrease in the body's defenses);
- detection of specific antibodies and T cells sensitive to tumor antigens in patients;
- the possibility of the formation of antitumor immunity and immunoproliferative diseases (with artificial administration of antibodies and suppression of immunity, respectively).
The protective function of immunity is not only the destruction of foreign agents (viruses, fungi and bacteria), but also the mutant cells from which tumors form. They are characterized by antigenic specificity, which depends on the cause of the appearance of the neoplasm:
- viruses (papillomas, leukemia and others);
- chemical carcinogens (methylcholanthrene, benzopyrene, aflotoxins and others);
- endocrine disorders (metabolic immunosuppression);
- physical environmental factors (all types of radiation).
Natural antitumor immunity has a very weak effect on the already formed malignant neoplasm. This is associated with the following factors:
- rapid tumor growth, ahead of the activation of immune forces;
- the selection by tumor cells of antigens that bind the corresponding receptors on the surface of killer lymphocytes;
- suppression of cellular immunity from the neoplasm.
Operating principle
The mechanism of antitumor immunity in medical science is still poorly understood. Although its protective function has been detected, antibodies can reflect tumor antigens without causing destruction of the malignant cells. In some cases, immunotherapy even gives the opposite effect, contributing to an increase in neoplasm.
According to modern concepts, activated macrophages and killer cells play a key role in this process. A feature of antitumor immunity is that it is characterized by a complex mechanism of interaction between the host organism and neoplasm. There are 4 main groups of factors:
- Antiblastoma - humoral and cellular (T-lymphocytes, TNF, macrophages, EC and K cells, specific antibodies, interferons, interleukins) that inhibit the development of the tumor and destroy its cells.
- Immunological resistance of the neoplasm, or its ability to withstand antitumor immunity.
- Problastoma: suppressing immunity (suppressor substances produced by macrophages and lymphocytes; hormone-like compounds, interleukin-10, circulating immune complexes, proteins of the TGFβ group, consisting of antigens, antibodies and complement components); enhancing immunity (TNF produced by macrophages; gamma interferon, interleukins 2 and 6, endothelial growth factor; immunodeficiency states).
Effector mechanisms
The main function of the effector mechanisms of antitumor immunity is the blocking and destruction of pathogens. There are 2 groups of receptors that selectively bind to specific antigens. Based on this, 2 types of effector mechanisms are also distinguished:
- Humoral, functioning due to soluble (humoral) factors - antibodies that bind and remove antigen.
- Cellular (antibody-independent), realized with the participation of cells of the immune system, the most important of which are T-lymphocytes, macrophages, NK-cells. They directly destroy foreign, infected and tumor cells.
If a pathologically altered cell escapes death when exposed to effector mechanisms, then a period of equilibrium may occur between its division and the overwhelming effect of immunity. With the progression of the malignant process, the tumor tissue comes out of the control of the immune mechanisms.
The most important role in the suppression of cell division is played by 2 types of lymphocytes that trigger the process of necrosis - T-lymphocytes and NK-cells that recognize the stress molecules that the tumor releases. T-lymphocytes form for a longer time, and their precursors recognize tumor antigens. Th1 lymphocytes trigger the inflammation mechanism, which leads to the activation of macrophages. The secretion products of the latter contribute to the disruption of local blood supply to tissues, which also leads to the death of tumor tissue.
The participation of T-lymphocytes is manifested in the impregnation of a malignant neoplasm with lymphoid cells, which destroy its cells by dissolution, or cytolysis. The activation of lymphocytes occurs under the influence of cytokines - protein information molecules with which they penetrate the tumor.
Among the internal factors inherent in the immune system of the human body, gamma interferon is also of great importance. Its functions are as follows:
- Suppression of tumor cell division.
- Activation of the process of their programmed death.
- Stimulating the production of cytokines, which attract T-lymphocytes to the neoplasm.
- Activation of macrophages and the development of T-helpers necessary to strengthen antitumor immunity.
- Suppression of the formation of new blood vessels, which impairs the nutrition of the tumor and contributes to a more rapid death of its cells.
Antitumor immunity: reasons for its low effectiveness
The growth of malignant neoplasms and their resistance to immunity are explained by the following reasons:
- poor ability to induce an immune response in tumor antigens;
- survival (natural selection) of immune-resistant tumor cells;
- constant modification of antigens;
- the presence of a capsule in the tumor;
- secretion of tumor antigens in soluble form, which leads to suppression of the immune response;
- the location of the neoplasm in places where the appearance of the antigen does not lead to an inflammatory immune response (the so-called “privileged” localization - the bone marrow, nervous, endocrine and reproductive systems, thymus);
- loss of some components of the effector system as a result of genetic or acquired (secondary) immunodeficiency conditions;
- the production of tumor cells of problastoma factors that suppress the immune system and contribute to the growth of tumors;
- in newborns - immaturity of effector systems, which entails the unrecognition of tumor cells.
These mechanisms of the ineffectiveness of antitumor immunity lead to the fact that the neoplasm becomes slightly immunogenic and is not perceived by the body as a foreign element. As a result, the protective reaction is reduced. Immune mechanisms cannot lead to rejection of an already formed malignant tumor.
Features
The features of antitumor immunity include:
- The main role in the immune response is played by T-lymphocytes, macrophages and NK cells that destroy tumor tissue. The value of humoral immunity is much less.
- Cancer antigens are recognized either directly by macrophages and dendritic cells responsible for innate and adaptive immunity, or through Th1 helpers.
- The interaction of the body and the tumor takes place in three directions: natural and acquired resistance to malignant neoplasms, immunosuppression from the side of the tumor. The combination of these factors constitutes antitumor immunity.
- Malignant cells in the process of natural selection acquire defense mechanisms against innate immunity. Their new phenotype is being formed, the neoplasm is evolving.
Tumor-associated antigens are divided into 2 groups - the first type (typical for many types of neoplasms, are of viral origin) and the second, very specific and detectable in all patients with this type of tumor.
One of the common features of antiviral and antitumor immunity is that it is both specific in nature, that is, directed against certain types of pathogens, and non-specific (destroys everything foreign to the body). Non-specific factors are mononuclear and NK cells, activated under the influence of interleukin 2 and interferons, as well as lymphokine-activated killer cells and cytokines.
Immunodiagnosis
In recent years, immunodiagnosis of malignant neoplasms has been used in medicine. It is based on the detection of the following protein compounds in the blood:
- antigens associated with tumors;
- antibodies;
- lymphocytes susceptible to tumor antigens.
Minimally invasive immunodiagnosis allows detecting cancer of various organs at an early stage of tumor development by the presence of specific antigens (the localization of the malignant neoplasm is indicated in brackets):
- PSA (prostate).
- P-53 (bladder).
- SCC (lungs, esophagus, rectum).
- CA-19-9 (pancreas).
- CA-125 (ovaries).
- CA-15-3 (mammary gland).
However, antibodies to a specific antigen in the blood of patients with cancer are infrequently determined (in 10% of cases). Immunoglobulins for tumor-associated antigens are detected more often - in 50% of patients. Currently, in the medical scientific environment, searches are being made for other antigens that help in the diagnosis of cancer.
Immunoprophylaxis and treatment
To increase antitumor immunity, immunomodulators are used that indirectly activate cells of the immune system:
- Interleukins 1 and 2. These protein compounds belong to the group of pro-inflammatory cytokines (information molecules) and are biologically active substances produced by white blood cells. Interleukins are the main participants in the process of forming the immune response when pathogens are introduced into microbiology. Antitumor immunity is activated due to the active division of lymphocytes (T-killers, NK-cells, T-helpers, T-suppressors and antibody producers). Interleukin 2 also activates the production of tumor necrosis factor.
- Preparations from the group of interferons. They stimulate the immune response by presenting antigens to T-lymphocytes that have been captured by macrophages and dendritic cells. T-helpers secrete protein information molecules that activate the work of other cells of the immune system. The result is an increase in antitumor immunity. Certain types of interferons (gamma-interferon) can directly affect macrophages and killers.
- Adjuvants. They are introduced together with the main immunobiological medicines and serve to enhance the response from the body's defenses. Most often they are used for healthy people with vaccination. One of the features of antitumor immunity in microbiology regarding this type of substance is that it can concentrate antigens on its surface. This provides a longer lasting effect. For targeted delivery of antigens to the organs of the lymphatic system, liposomes are used - vesicles with lipid biolayers. The most common substances of this group are Freund's complete and incomplete adjuvant, aluminum hydroxide, whooping cough, precipitated on aluminum alum; Polyoxidonium.
- Elements of bacterial cells (immunostimulants Prodigiosan, Likopid, Romurtid and others).
Animal experiments show that the introduction of tumor antigens leads to the formation of immunological memory. As a result, the transplanted malignant tumor is rejected after that. In recent years, active development has been carried out in medicine, which will make it possible to create an anti-tumor immune memory through vaccination. So far, one type of vaccination has been created in this direction - to increase immunity to human papillomaviruses, which induce the occurrence of cervical cancer in women (Gardasil and Cervarix of foreign manufacture).
Types of tumors
Immunotherapy is effective against the following types of tumors:
- melanoma arising from melanocytes - pigment cells;
- non-Hodgkin lymphomas originating from lymphocytes;
- cancer of the kidneys, rectum, ovaries;
- hairy cell leukemia (damage to B-lymphocytes, white blood cells);
- glioma (brain tumor);
- soft tissue sarcoma, the origin of which is associated with epithelial cells and connective tissue.