The recognition problem: the role of PAMP and MHC molecules
Tumor cells initially exhibit extremely low immunogenicity. This is because they do not express PAMPs (pathogen-associated molecular patterns) typical of microorganisms. Dendritic cells capture tumor epitopes and present them to T cells, but without PAMPs, this process lacks pro-inflammatory stimulation. As a result, dendritic cells produce little IL-12 and weakly express costimulatory molecules (CD80 and CD86). Instead of full T-cell activation, anergy (unresponsiveness) develops.
The second critical factor is the altered expression of major histocompatibility complex (MHC) molecules. The effectiveness of an attack depends on which receptors are presented on the tumor membrane:
- Successful attack: the cell expresses a tumor epitope along with classical MHC-I molecules (A, B, C). It is recognized and destroyed by a cytotoxic CD8+ T lymphocyte.
- Loss of all MHC molecules: during progression, the tumor may lose MHC-I molecules and begin expressing stress molecules. T lymphocytes no longer see it, but it becomes an ideal target for NK cells (natural killers).
- "Ideal escape": the tumor loses classical MHC-I molecules but retains non-classical ones (e.g., HLA-G or E). The absence of classical molecules makes it invisible to T killers, while the presence of non-classical ones blocks the activity of NK lymphocytes. Immune surveillance is completely bypassed.
Active suppression: soluble antigens and cytokines
In addition to camouflage, the tumor switches to active defense by secreting various blocking factors into the microenvironment. These substances prevent recognition and subsequent cytolysis:
- Suppressor cytokines. The tumor actively synthesizes IL-10, TGFβ (transforming growth factor beta), and prostaglandin E, which directly suppress immune responses.
- Soluble antigens. Shed or actively secreted antigens bind antibodies and lymphocyte receptors at a distance. The resulting immune complexes inhibit the humoral response via an FcR-dependent mechanism (which is especially significant in leukemias).
- Soluble stress proteins (MIC family). This is a crucial self-defense factor. MIC molecules block activating NKG2D receptors on the surface of NK cells. At the same time, the expression of these receptors on the tumor itself can be suppressed.
Additionally, secreted factors cause a blockade of the $\zeta$-chain (zeta-chain) expression in the lymphocyte receptor complex, leading to a complete loss of the functional activity of tumor-infiltrating lymphocytes.
There is also a mechanism of antigenic modulation (internalization of complexes). If antibodies are produced against a tumor antigen, they bind to it on the membrane, after which the entire complex is internalized into the cell. Reduced surface expression of the antigen protects the cell from T killers.
Microenvironment and activation of regulatory T cells
The tumor purposefully creates a favorable microenvironment around itself. To stimulate its own growth and nutrition, it synthesizes epidermal, platelet, and fibroblast growth factors. Stroma development and angiogenesis are driven by vascular endothelial growth factor (VEGF).
Against the backdrop of tumor growth, massive activation of regulatory T cells (Tregs) occurs. In regional lymph nodes and the tumor microenvironment itself, the following accumulate:
- Natural and induced Tregs (including Th3).
- Cells with the specific phenotype CD4+CD25hiFOXP3+.
Entering into direct contact with dendritic cells, Tregs secrete immunosuppressive cytokines (primarily TGFβ and IL-10), leading to severe suppression of effector T lymphocytes of both CD8+ and CD4+ classes.
Pathways to enhance antitumor defense
Although tumor microenvironment factors severely limit the immune response, the development of immunotherapy approaches continues. There are two main directions:
1. Enhancing tumor immunogenicity. In the 1970s, physicians attempted to add PAMP effects to weak tumor immunogens using adjuvants (mycobacteria, BCG vaccine, Corynebacterium parvum). Today, the main vector is the creation of antitumor vaccines based on dendritic cells. They are loaded with antigens in vitro and treated with stimuli that reduce tolerogenicity.
2. Enhancing effector mechanisms. Ready-made effector products (monoclonal antibodies, cytotoxic cells) or factors promoting their active generation in vivo are introduced into the patient's body.
Briefly: answers to topical questions
What mechanisms of cytotoxicity do CD8+ T lymphocytes use to destroy tumor cells?
CD8+ T lymphocytes use two main mechanisms of contact cytolysis to destroy target cells.
- Perforin-dependent mechanism — involves the formation of an immune synapse, degranulation, and insertion of perforin into the membrane to form pores. Granzymes and granulysin penetrate through them, triggering apoptosis via caspases and the sphingomyelin pathway.
- Fas-dependent cytolysis — a receptor mechanism for inducing apoptosis without granule exocytosis. It is carried out through direct contact, in which the Fas ligand of the T lymphocyte binds to the Fas receptor of the target cell, transmitting a lethal signal.
What inhibitory receptors (immune checkpoints) are expressed on exhausted tumor-infiltrating lymphocytes?
The main inhibitory receptors (immune checkpoints) include:
- CTLA-4 (CD152) — binds to the costimulatory molecule B7 with higher affinity than the CD28 receptor, inhibiting T-cell activation and IL-2 secretion.
- PD-1 — interacts with its PD-L ligands and in most cases causes immune cell inhibition, allowing the tumor to evade the immune response.
What are the main classes into which tumor antigens recognized by the immune system are divided?
Tumor antigens are divided into several main classes depending on their origin and expression characteristics.
- Viral — antigens of tumor-causing viruses.
- Mutant — products of mutant genes that normally control apoptosis and the cell cycle.
- Cancer-testis antigens (Cancer-testis antigen) — antigens expressed in embryos and adult gonads.
- Differentiation — normal organ-specific antigens with sharply increased expression.
- Amplified — normal but overexpressed antigens.
- Products of aberrant processing — normal antigens with excessive glycosylation.
Class and exam questions
Due to the lack of PAMP molecules in tumors, antigen presentation occurs without the necessary pro-inflammatory stimulation. Dendritic cells release little IL-12, leading to T-lymphocyte anergy.
Due to the lack of PAMP molecules in tumors, antigen presentation occurs without the necessary pro-inflammatory stimulation. Dendritic cells release little IL-12, leading to T-lymphocyte anergy.
What is the "perfect escape" phenomenon?
The tumor loses classical MHC-I molecules to avoid attack by CD8+ T killers, but retains non-classical ones (e.g., HLA-G), which block the reaction by NK cells.
How do soluble antigens protect the tumor?
Soluble forms of tumor antigens bind to lymphocyte receptors at a distance and neutralize antibodies. The resulting immune complexes suppress the humoral response via FcR-dependent mechanisms.
What else to study on this topic
- Mechanism of T-cell anergy development during defective antigen presentation
- The role of cofactors in initiating a response to allogeneic tissues without PAMP participation
- Antigenic modulation using the example of the TL antigen in T-cell lymphomas
- Biology of tumor-infiltrating lymphocytes and $\zeta$-chain blockade
- Mechanisms for creating antitumor vaccines based on dendritic cells
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