Tumor immunology

Mechanisms of antitumor defense

The primary role in the destruction of transformed cells is played by cellular immunity factors — natural killer (NK) cells and cytotoxic T lymphocytes. An important regulator is the cytokine IFNγ. It activates macrophages, stimulates the development of Th1 cells, suppresses blood vessel growth (angiogenesis), and induces cells to secrete the chemokines CXCL9 (MIG) and CXCL10 (IP-10). These chemokines attract T lymphocytes expressing the CXCR3 receptor to the lesion.

A humoral response is also formed, but it has no protective effect. The complement system is disrupted by surface cell factors, and macrophages are poorly recruited due to the lack of an appropriate inflammatory background. Moreover, there is an "enhancing effect" (enhancing effect): antibodies can shield target antigens, physically protecting the neoplasm from attack by effector cells. Nevertheless, antibodies are actively used in diagnostics. The use of panels consisting of several antigens significantly increases accuracy: for example, in colorectal cancer, a panel of 13 antigens increases sensitivity to 46%, whereas individually they yield only 3–8%. Antibodies are also used to create targeted drugs — immunotoxins.

Tumor progression and immune evasion

A formed tumor functions as a separate organ with its own stroma. During growth, antigenic simplification occurs — the diversity and expression intensity of antigens on the cell surface decrease. The interaction between the neoplasm and the body is described by the "Three Es" concept:

1. Elimination — successful recognition and rejection of foreign cells.
2. Equilibrium — containment of growth without complete destruction.
3. Escape — the tumor overcomes defenses and begins to grow uncontrollably.

To suppress immunity, malignant cells secrete factors that block the expression of the ζ-chain (zeta chain) of the lymphocyte receptor complex, depriving them of functional activity. The tumor also recruits regulatory T cells (Tregs), including the CD4+CD25hiFOXP3+ and Th3 phenotypes. They accumulate in regional lymph nodes and the microenvironment, releasing immunosuppressive cytokines TGFβ and IL-10, which inhibit the function of effector T lymphocytes. To improve its own nutrition, the tumor secretes growth factors, including vascular endothelial growth factor (VEGF).

Tumor antigens and stress molecules

The main reason for the weakness of the antitumor response is the absence of PAMPs (pathogen-associated molecular patterns) on malignant cells. Without these danger signals, innate immunity cannot fully mobilize to initiate an adaptive response.

Antigens are divided into:

• B antigens: recognized by antibodies, convenient for serological testing.
• T antigens: recognized by T lymphocytes, of the greatest interest for actual protection. Molecules with B epitopes almost always contain T epitopes as well.

In addition to classical antigens, non-classical stress molecules MICA and MICB appear with high frequency on the surface of transformed cells. They are encoded by MHC class I genes, but lack the light chain (β2-microglobulin) and the peptide-binding groove. Normally, they are present only on certain intestinal cells, but during stress or tumor growth, their expression increases sharply. These molecules are polyclonally recognized by NK cells and γδ T lymphocytes.

Immune activation pathways (Immunotherapy)

Since the immune system cannot independently reject a formed tumor, methods of artificially enhancing defense are being developed. Work is underway in two directions:

1. Enhancement of immunogenicity. Historically, adjuvants with bacterial components (BCG vaccine, Corynebacterium parvum) were used for this purpose to provide the missing PAMP signal to the tumor. A modern approach is the creation of vaccines based on dendritic cells. They are extracted, loaded with tumor antigens in vitro, treated with stimulators to reduce tolerogenicity, and returned to the body.
2. Enhancing effector mechanisms. The patient is administered ready-made antibodies, cytotoxic cells, or factors stimulating their formation in vivo.

The formation of T-cell memory (involving CD8+ and CD4+ cells) has been experimentally proven, which is capable of rejecting a re-transplanted syngeneic tumor. This resistance can even be adoptively transferred to naïve recipients along with T cells. This opens up prospects for the creation of effective prophylactic vaccines in the future.

Class and exam questions

What else to study on this topic

• Mechanisms of self-tolerance formation (role of the thymus and peripheral anergy).
• Primary and secondary immunodeficiencies as a risk factor for tumor development.
• The role of cytokines TGFβ and IL-10 in the immunosuppression of the tumor microenvironment.
• Characteristics of immunologically privileged sites in the body.
• Principles of creating dendritic cell-based antitumor vaccines.

Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.