Cancer Biology Chapter 15

Describe the role of the immune system in preventing/controlling cancer and describe the evidence for cancer immunosurveillance, including observations that support the idea that the immune system can eliminate neoplastic cells before tumors become clinically apparent.

The immune system’s primary role in cancer is immunosurveillance, a process where the body continuously scans tissues to identify and eliminate nascent neoplastic cells before they develop into clinically detectable tumors. Strong evidence for this includes the significantly higher incidence of various cancers in immunocompromised individuals (like transplant patients or those with HIV) compared to the general population. Furthermore, the presence of tumor-infiltrating lymphocytes (TILs) within a tumor is often a positive prognostic indicator, suggesting that a vigorous immune response can actively edit tumor growth or keep it in a state of equilibrium.

Explain antigen presentation and how the body normally recognizes cells presenting foreign antigens or neoantigens.

Antigen presentation is the mechanism by which cells display internal protein fragments on their surface using Major Histocompatibility Complex (MHC) molecules for T-cell inspection. Recognition occurs when a T-cell receptor binds to an MHC molecule displaying a neoantigen, a foreign peptide resulting from a mutation in the cancer cell’s DNA. Since these neoantigens are unique to the tumor and have not been seen by the immune system during development, they trigger a non-self signal that activates an immune attack, provided the T-cell has the corresponding specific receptor.

Understand immune tolerance and how our immune system distinguishes self from non-self.

Immune tolerance is a protective mechanism that prevents the immune system from attack healthy “self” tissues. It is established through central tolerance in the thymus, where developing T-cells that react strongly to self-antigens are eliminated (apoptosis), and peripheral tolerance, where escaped self-reactive T-cells are suppressed or made anergic (inactive). The systemm distinguishes self from non-self by retaining only the T-cells that ignore normal proteins but remain capable of recognizing foreign entities or mutated neoantigens, ensuring that the immune response is precisely targeted at “altered” cells.

Be able to explain cross presentation and its importance for controlling cancer.

Cross-presentation is a specialized process where dendritic cells (professional APCs) take antigens they have eaten from the extracellular environment and present them on MHC-I molecules instead of the usual MHC-II. This is critical for controlling cancer because CD8+ cytotoxic T-cells can only be activated by antigens displayed on MHC-I. Since naive T-cells often cannot interact directly with a hiding tumor, cross-presentation allows dendritic cells to “prime” these killer T-cells by showing them exactly what the cancer neoantigens look like, effectively licensing them to go out and destroy the tumor.

Explain the basics of how our body activates cytotoxic T cells in response to foreign entities (including cancer cells).

Activation of a cytotoxic T cell requires a two-signal handshake to ensure a precise attack. Signal 1 occurs when the TCR specifically binds to a neoantigen presented on MHC-I. Signal 2 is a co-stimulatory signal where the CD28 receptor on the T cell binds to B7 proteins on a professional APC. A naive T cell is one that has never encountered its specific antigen; once it receives both signals, it becomes a primed T cell, which undergoes rapid clonal expansion and gains the ability to kill. The killing mechanism involves the release of perforin to create pores in the target cell membrane and granzymes to enter those pores and trigger extrinsic apoptosis via the caspase cascade.

How do cancer cells suppress antigen presentation to evade the immune system?

Cancer cells can become invisible to the immune system by physically removing the machinery required for T cells to recognize them. This is primarily achieved through the loss of MHC-I expression on the cell surface or the suppression of TAP1, the transporter protein responsible for loading neoantigen peptides into the MHC molecules. Without a functional MHC-I/peptide complex, cytotoxic T cells cannot identify the cell as cancerous, allowing the tumor to proliferate without triggering an attack from the body’s primary immune assassins.

What is the difference between M1 and M2 macrophages in the tumor environment?

The immune system’s response to a tumor depends heavily on the polarization of macrophages. M1 macrophages are pro-inflammatory attackers that identify and help destroy tumor cells. However, tumors often manipulate the microenvironment to shift these into M2 macrophages, which are “wound-healing” cells. M2 macrophages are highly pro-tumor; they actively suppress T-cell activity, promote angiogenesis (vessel growth), and facilitate tissue remodeling, effectively turning a potential immune defense into a support system for tumor growth and invasion.

How do cancer cells use FasL to suppress the immune response?

Some cancer cells engage in a lethal “counter-attack” against the immune system by expressing FasL on their surface. When an attacking cytotoxic T cell, approaches the tumor, its Fas receptor binds to the cancer cell’s FasL. Instead of the T cell killing the cancer, this interaction triggers a signaling cascade that induces apoptosis in the T cell. By secreting or expressing FasL, the tumor effectively kills off the very cells sent to destroy it, creating a “no-go zone” for immune defenders.

How does the recruitment of regulatory T cells (Tregs) help a tumor evade the immune system?

Cancer cells often secrete specific chemokines to actively recruit Tregs into the tumor microenvironment. While Tregs normally exist to prevent autoimmunity by keeping the immune system in check, in the context of cancer they act as a biological shield from the tumor. Once present, Tregs release inhibitory cytokines and use surface receptors to actively suppress the activity of cytotoxic T cells and helper T cells nearby, preventing them from mounting an effective anti-tumor response.

Explain what immune checkpoints are and how they inhibit T cell activation or killing.

Immune checkpoints are a collection of “off-switch” surface receptors, such as CTLA-4 and PD-1, that the immune system normally uses to prevent over-activation and maintain self-tolerance. CTLA-4 acts as an early-stage checkpoint in the lymph nodes by outcompeting CD28 for B7 binding, effectively blocking the signal 2 required for a naive T cell to be primed. In contrast, PD-1 acts as a late-stage checkpoint on the surface of already-activated T cells; when it binds to its ligand PD-L1 (often overexpressed by cancer cells), it sends an inhibitory signal that induces T-cell exhaustion. By hijacking these natural “brakes,” cancer cells can physically survive the presence of cytotoxic T cells, creating an immunosuppressive shield that prevents the immune system from completing the killing process.