Immunity and Neoplasm Interaction
The dynamics of the standoff between the immune system and malignant cells proceeds in three sequential stages:
- Elimination. At early stages, defense systems successfully recognize and destroy transformed cells, preventing the disease from developing.
- Equilibrium phase. If some cells survive, a peculiar balance is established. Immunity restrains growth, but the tumor potential remains. This period can last a very long time.
- Progression (escape). The neoplasm completely gets out of control, overcomes defense barriers, and begins to grow actively.
Key cells and cytolysis mechanisms
The primary task of destroying malignant cells is undertaken by cytotoxic lymphocytes.
Natural killer (NK) cells act instantaneously, without prior maturation. They recognize cellular stress molecules MICA and MICB on the tumor surface, reacting polyclonally.
Cytotoxic T lymphocytes (CTLs), by contrast, take time. Their precursors — naïve CD8+ T lymphocytes — must receive antigen information from dendritic cells (in complex with MHC-I molecules). Interleukin-2 (IL-2), supplied by type 1 T helpers (Th1), is required for their differentiation and proliferation.
Destruction of targets occurs via three main pathways:
- Contact cytolysis: classic release of perforins and granzymes.
- Fas-dependent apoptosis: interaction of the Fas receptor on the tumor with FasL on lymphocytes.
- TRAIL-mediated apoptosis: transmission of a death signal through the contact of the TRAIL molecule (on NK cells, monocytes, or dendritic cells) with the death receptor DR5 on the tumor surface.
The role of helpers: T helper and γδ T cells
Accessory cells do not kill the tumor directly, but create conditions for its destruction.
CD4+ T lymphocytes (Th1) not only help killers mature, but also trigger focal "immune inflammation". They activate macrophages, which ultimately leads to local vascular thrombosis, disruption of tumor nutrition (trophism), and its indirect death.
γδ T cells also participate in defense. The exact mechanism of their work is not fully understood, but direct cytolysis is hypothesized. The importance of these cells has been proven in experiments: mice lacking genes for the γ or δ chains of the receptor get cancer much more often than animals with defects in classical αβ receptors.
Interferon-gamma — the main molecular weapon
The most important endogenous factor of antitumor defense is interferon-gamma (IFNγ). It is initially secreted by NKT cells, and subsequently by NK and Th1 lymphocytes.
How IFNγ works:
- Stops division: stimulates the production of p21 and p27 proteins, which block cell cycle enzymes (kinases Cdk2 and Cdk4).
- Triggers self-destruction: induces caspase 1 as well as Fas receptors on the tumor.
- Directs the target: forces cells to secrete chemokines CXCL9 and CXCL10, which lure fresh T lymphocytes with the CXCR3 receptor to the focus.
- Finishes off: suppresses vessel growth (angiogenesis) and activates macrophages.
Why does immunity lose?
Despite a powerful arsenal, an established tumor rarely disappears on its own. The main reason lies in the ability of malignant cells to evade attack and suppress the activity of defenders.
A telling example is tumor-infiltrating lymphocytes (TILs). These are T cells (mainly CD8+) that have managed to penetrate deep into the neoplasm. In vivo (in vivo), they are functionally paralyzed due to the loss of structural receptor elements (usually the ζ chain). If extracted and treated with cytokines (IL-2) in vitro, their ability to kill cancer cells is restored.
Humoral response (antibodies) is also ineffective. The complement system is blocked by membrane defense factors, and macrophages respond poorly to antibodies without pronounced inflammation. Worse still, the "tumor growth enhancement" phenomenon occurs: antibodies settle on tumor antigens, physically hiding them from deadly T killers. Therefore, antibodies are used today mainly for diagnostics (as tumor markers) or as artificial targeted drugs (immunotoxins).
Briefly: answers to topical questions
What molecules make up the TCR receptor complex and why are they lost in tumor-infiltrating lymphocytes?
The T lymphocyte receptor complex is a single structure consisting of the TCR antigen-recognizing dimer, the CD3 complex, the CD247 ζ dimer, and coreceptors.
The complex includes:
- TCR antigen-recognizing dimer — includes variable and constant domains of α and β chains.
- CD3 complex — forms εγ and δε heterodimers.
- CD247 ζ dimer — a ζζ homodimer located in the center of the complex.
- Coreceptors — CD4 or CD8.
In tumor-infiltrating lymphocytes (TILs), the expression of TCR complex chains, usually the ζ chain and less frequently the ε chain, is blocked. This leads to their functional inertia. The cause of such blockade is not described in the sources.
Which immune checkpoints are expressed on the surface of exhausted T lymphocytes?
Exhausted T lymphocytes are not mentioned in the sources, but immune checkpoints expressed on activated T cells and tumor cells are described.
These include:
- CTLA-4 receptor (CD152) — a suppressive receptor that moves to the T-cell membrane in the late activation period and promotes the "disassembly" of the immune synapse.
- Programmed cell death ligand 1 (PDL1) — expressed by the tumor itself rather than T lymphocytes; its evaluation is important for prescribing immune checkpoint inhibitors.
Receptors containing ITIM cytoplasmic sequences can also perform a suppressive function.
Class and exam questions
Why don't antibodies destroy the tumor?
The humoral response has no protective effect. Factors on the cell surface destroy complement components, and phagocytes are weakly recruited due to a shortage of pro-inflammatory signals. Sometimes antibodies even "shield" the tumor from T lymphocytes.
What are tumor-infiltrating lymphocytes (TILs)?
These are lymphocytes (predominantly CD8+) that have penetrated into the tumor tissue. In vivo, they are in a dormant state due to the loss of receptor ζ chains, but in vitro their activity can be restored using cytokines.
How is antitumor memory formed?
After meeting antigens, memory T cells (both CD8+ and CD4+) are formed. In experiments, they ensure rejection upon re-transplantation of the same tumor. Antitumor vaccines are being developed based on this principle.
What else to study on this topic
- Mechanisms of tumor immune escape
- Processing and presentation of tumor-specific antigens
- Structure and functions of TRAIL and DR5 molecules
- Principles of creating targeted immunotoxins
- The role of LAK cells in the tumor microenvironment
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