Tumor antigens

Main classes of tumor antigens

Based on their origin, tumor-associated antigens are divided into several large groups. Each has its own expression characteristics and clinical significance:

• Viral. These are the gene products of viruses that act as tumor causative agents. Examples: EBNA (Epstein-Barr virus), E6 and E7 (human papillomavirus), HHV-8.
• Mutated (unique). Products of mutant genes that control the cell cycle and apoptosis in healthy cells. They are extremely rare and specific to a particular tumor (p53, Cdk4, Cas8, β-catenin).
• Cancer-testis antigens (CTA). Expressed in embryos and adult gonads (testes). They include the MAGE (1–12) series, BAGE, GAGE, NY-ESO-1, and SSX2.
• Differentiation antigens. Normal organ-specific antigens (Melan A/VART-1, tyrosinase, gp100, PSA, ANKRD30A, GFAP, TG).
• Amplified. Normal molecules whose expression is unbalanced and enhanced. These include the HER-2/neu receptor, BIRC apoptosis inhibitors, cyclins B1 and D1, and Bcr/Abl.
• Products of abnormal processing. Normal antigens subjected to excessive glycosylation (the MUC-1 – MUC-7 family).

Features of the p53 tumor suppressor and embryonic markers

The p53 protein in a healthy cell monitors DNA integrity and triggers apoptosis upon unreparable breaks. Normally, the molecule is detected extremely rarely. However, in approximately 50% of malignant neoplasms, the p53 gene is mutated. As a result, a non-functional protein with an increased lifespan is synthesized.

Mutant p53 itself is found in 20–35% of tumors, and antibodies against it are detected in serum in 15–20% of cases. An important immunological feature is that the B-epitope of the protein does not change upon mutation, so antibodies bind equally well to both normal and defective molecules.

A widespread variant is embryonic antigens, particularly cancer-testis antigens (CTA). More than 40 families of CTA genes have been identified (with 1–12 genes in each). They are detected using testicular gene libraries and bioinformatics analysis. Historically, the first discovered antigen was MAGE-1 (the largest family, cloned via T-cell epitopes), which marks melanoma cells. In tumor cells, representatives of this group are expressed in only 5–10% of cases.

Alteration of molecular properties and autotolerance

Malignant growth is often accompanied by a sharp increase in the expression of differentiation antigens, which disrupts natural autotolerance. The immune system reacts with an autoimmune process, damaging normal tissues. A classic clinical example is paraneoplastic neurological syndromes, which arise due to cross-reactivity of antibodies against onconeural antigens with cells of the nervous system.

Antigenic properties can also arise due to excessive glycosylation. For example, mucins (the MUC family) are proteins with repeating domains containing O-glycosyl groups separated by cysteine. Normally, they function as adhesion molecule receptors. In oncology, their altered forms are characteristic of intestinal carcinomas and are capable of inducing both cellular and humoral immune responses.

Principles of tumor immunodiagnostics

Tumor antigens more often indicate the presence of a malignant process in general rather than a specific type of tumor.

• In clinical practice, it is more convenient to detect not the antigens themselves on cells, but serum autoantibodies against them (recognizing B-epitopes). This is technologically simpler and has high specificity.
• The main drawback is that antibodies to one specific antigen are rare (about 10%).
• Antigen panels are used to increase accuracy. For example, in colorectal cancer, a panel of 13 markers raises diagnostic sensitivity from 3–8% (for each individual protein) to a cumulative 46%.

The fundamental problem of the immune response lies in the fact that tumor antigens do not contain PAMPs (pathogen-associated molecular patterns). Without PAMPs, innate immunity factors are not mobilized, which prevents the adequate initiation of an adaptive T-cell response (recognition of T-antigens), which is of the utmost importance for real antitumor defense.

Stress molecules and the Three Es concept

In addition to classical antigens, tumors express non-classical stress molecules MICA and MICB. Genetically, they are encoded in the MHC-I locus and are similar to them in tertiary structure, but lack the light chain (β2-microglobulin) and the peptide-binding groove. Normally, they are present only on certain intestinal cells. Under stress, viral infection, or tumor growth, they appear in large numbers and are polyclonally recognized by NK cells and γδ T lymphocytes.

A formed tumor is a peculiar organ with its own stroma. During tumor progression, cells acquire autonomy and undergo antigenic simplification — a decrease in the diversity and intensity of antigen expression, leading to immunological tolerance.

The dynamics of the interaction between the tumor and the immunity is described by the "three Es" concept:

1. Elimination: immunological rejection of cells that are antigenically foreign.
2. Equilibrium: immunity restrains but does not completely destroy the tumor.
3. Escape: the tumor overcomes immune control and continues to grow.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of overexpression of HER-2/neu proteins and cyclins during tumor growth.
• The role of stress molecules MICA and MICB in interaction with natural killer (NK) cells.
• Pathogenesis of paraneoplastic neurological syndromes due to cross-reactive autoimmune responses.
• Use of serum autoantibodies in early screening diagnostics of colorectal cancer.
• Overlap of T- and B-cell epitopes on tumor antigen molecules.

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

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