Concept of immune surveillance and the role of NK cells
Around one million mutant cells capable of malignant transformation are formed in the body daily. The low incidence of clinical tumors is explained by their timely elimination through immune surveillance mechanisms. T lymphocytes are able to recognize foreign molecular structures as "altered self".
Interesting data have been obtained from studying nude mice, in which T-cell development is impaired due to the absence of the thymus. Despite this, the incidence of tumors in such animals is not increased. Resistance is provided by NK cells, which perform alternative immune surveillance functions. However, this concept has detractors and is not universally accepted among oncologists; the tumor survival paradox is explained by the fact that without immune surveillance, their number would be significantly greater.
Relationship between immunity and viral-induced tumors
The protective role of immunological mechanisms has been proven for neoplasms of viral etiology. Several prominent examples are identified in humans:
- Cervical cancer is closely linked to papillomavirus infection.
- Lymphomas and immunoblastic tumors develop under the influence of the Epstein–Barr virus.
- Kaposi sarcoma is triggered by human herpesvirus type 8 (HHV-8).
Additional evidence for the effectiveness of immune defense is provided by data on the use of immunosuppressants in organ transplantation. Long-term administration of such drugs increases the risk of non-viral tumors (melanoma, kidney, colon, lung, and endocrine cancers) by 3–25 times.
Tumor antigens and diagnostics
The first evidence for the existence of specific antigens is associated with the work of G.I. Abelev, who discovered alpha-fetoprotein, and Yu.S. Tatarinov. Tumor markers are divided into secreted serum and membrane-bound forms.
Main serum tumor-associated antigens:
- Carcinoembryonic antigen (used in neoplasms of the colon).
- Prostate-specific antigen (PSA).
- Human chorionic gonadotropin (detected in choriocarcinoma and seminoma).
Their appearance is based on the pathological reactivation of genes active only during the embryonic period. To search for such antigens, both classical T-lymphocyte assays and modern SEREX technology, based on the screening of gene libraries using serum autoantibodies, are employed.
Immune dependence and tumor infiltration
The presence of tumor transplantation antigens determines the sensitivity of neoplasms to defense reactions, although such structures are not always detected. A group of immune-dependent tumors is distinguished, which includes viral neoplasms, melanoma, kidney cancer, and breast cancer. At the same time, gastric cancer and small cell lung cancer remain practically independent of immunological mechanisms.
An important prognostic factor is TIL (tumor-infiltrating lymphocytes). The intensity of tumor tissue infiltration by lymphocytes positively correlates with patient survival rates and serves as an independent prognostic sign.
Briefly: answers to topical questions
What mechanisms allow tumor cells to evade immune surveillance?
Tumor cells evade immune surveillance using mechanisms that hinder their recognition and suppress the effector responses of the immune system.
- Alteration of histocompatibility molecule expression (MHC) — loss of classic MHC-I while retaining non-classic molecules makes the cell inaccessible to CD8+ T cells and NK cells.
- Antigen mutation or modulation — disappearance of the tumor antigen from the cell surface.
- Lack of pattern expression (PAMP) — reduces tumor immunogenicity and can lead to T-cell anergy.
- Suppression of lymphocyte activity — blockade of ζ-chain expression and other receptor complex chains causes functional inertness of tumor-infiltrating lymphocytes.
- Activation of regulatory T cells (Treg) — secretion of immunosuppressive cytokines TGF-β and IL-10 and suppression of effector T lymphocytes.
- Indoleamine 2,3-dioxygenase (IDO) — catalyzes the conversion of tryptophan into kynurenine, causing tryptophan depletion, kynurenine accumulation, and cell cycle arrest.
Which membrane tumor-associated antigens are expressed on the surface of malignant cells?
The cited sources directly indicate the following molecules expressed on the surface of tumor cells:
- Stress molecules MICA and MICB — non-classical molecules expressed by tumor cells and recognized by NK cells and γδ T lymphocytes.
Sources also indicate that membrane tumor markers are associated with tumor cells, but do not provide a complete list of membrane localization for all listed antigens.
By what molecular mechanisms and substances do NK cells destroy tumor targets?
Natural killer cells destroy tumor targets via contact lysis, inducing apoptosis through several pathways.
- Perforin-dependent mechanism — exocytosis of granules into the immune synapse. Perforin polymerizes and forms pores in the target membrane. Through these pores, granzyme B (activates caspase 3 and Bid factor) and granulysin (triggers apoptosis via the sphingomyelin pathway) enter.
- Receptor mechanism — induction of apoptosis via TNF and TNFR family molecules through the interaction of NK cell ligands (FasL, TRAIL, membrane form of TNF) with target receptors.
- Antibody-dependent cellular cytotoxicity (ADCC) — initiation of lysis upon recognition by the FcγRIII (CD16) receptor of antibodies of subclasses IgG1 and IgG3 opsonizing the tumor cell.
Class and exam questions
What is the concept of immune surveillance and what is the role of NK cells in it?
The concept describes the elimination of a million mutant cells daily by T lymphocytes. Using the example of athymic nude mice, it has been proven that NK cells perform alternative immune surveillance, providing protection even in the case of T-cell deficiency.
Which human viral tumors are proven to be associated with immune defense?
These include cervical cancer (papillomavirus), lymphomas and immunoblastic tumors (Epstein–Barr virus), as well as Kaposi sarcoma caused by human herpesvirus type 8.
Which tumor markers belong to secreted antigens?
These include alpha-fetoprotein, carcinoembryonic antigen, prostate-specific antigen (PSA), and human chorionic gonadotropin.
What is the clinical significance of TILs (tumor-infiltrating lymphocytes)?
The intensity of tumor lymphocyte infiltration positively correlates with patient survival time and is an independent prognostic sign.
What else to study on this topic
- Mechanisms of tumor evasion from the immune response
- Principles and prospects of tumor immunotherapy
- The role of cytokines in the regulation of antitumor immunity
- Comparison of SEREX technology with classical methods of antigen identification
- Features of the humoral response during tumor growth
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