Tumours are remarkably adept at evading immune detection and destruction, employing diverse strategies to suppress, misdirect, or escape immune responses. For biomedical science students, understanding these tactics is crucial to unraveling how tumors grow unchecked. Here’s a breakdown of the main immunoevasion mechanisms:
1. Hiding Identity
Tumors evade immune recognition by suppressing Tumor-Specific Antigens (TSA) and Tumor-Associated Antigens (TAA) expression, key markers the immune system uses to identify cancer cells. However, certain TSA/TAA, such as HER2, are vital for tumor survival, making this strategy selective.
To avoid detection:
- MHC-I Expression Suppression: MHC-I molecules are essential for presenting TSA/TAA to cytotoxic T cells. Tumors:
- Inhibit TAP1/2: Blocking these transporters stops antigen transport to the endoplasmic reticulum (ER).
- Inhibit β2-microglobulin (β2m) Synthesis: Prevents MHC-I-peptide complexes from being expressed on the cell surface.
- Suppress MHC-I Transcript Production: Halts MHC-I protein synthesis entirely.
However, the loss of MHC-I can activate Natural Killer (NK) cells, forcing tumors to adopt further strategies.
2. Hiding Stress
NK cells are activated by the absence of MHC-I and the presence of stress markers. Tumors adapt by:
- Suppressing MHC-I selectively while secreting fewer stress proteins to reduce NK activation.
- Releasing decoy stress proteins (e.g., MIC-A) to misdirect NK cells.
- Expressing Killer Inhibitory Receptors (KIRs) or modulating NKG2D pathways to deactivate NK cells.
3. Avoiding Apoptosis
Immune cells induce apoptosis via Fas ligand (FAS-L), granzymes, or complement systems. Tumors evade this by:
- Becoming resistant to FAS-L or granzyme signaling.
- Overexpressing membrane-bound Complement Regulatory Proteins (mCRPs) to shield against complement-mediated apoptosis.
4. Creating an Immunosuppressive Microenvironment
Tumors manipulate the surrounding environment to suppress immune cell activity:
- Recruiting Regulatory T cells (Tregs): Tumors secrete CCL22, attracting Tregs to suppress effector T cells (Teffs) or induce their apoptosis.
- Depleting Tryptophan: By secreting indoleamine 2,3-dioxygenase (IDO), tumors prevent T cell activation.
- Expressing PD-L1: This ligand binds PD-1 on T cells to suppress their activity or interacts with CTLA-4 to block co-stimulatory signals.
Tumor-Associated Macrophages (TAMs):
Tumors exploit macrophages, creating a “wound-like” environment with actively tolerogenic macrophages that secrete TGF-β and VEGF to prevent immune attack. Hypoxia further polarizes TAMs toward an immunosuppressive M2-like phenotype.
Myeloid-Derived Suppressor Cells (MDSCs):
Altered myelopoiesis induced by tumor factors (e.g., GM-CSF, IL-6) generates MDSCs. These cells suppress immunity through:
- Secreting nitric oxide (NO), reactive oxygen species (ROS), and arginase.
- Preventing differentiation into dendritic cells (DCs).
5. Killing Immune Cells
Tumors directly attack immune cells through:
- FAS-L Expression: Killing T cells and antigen-presenting cells (APCs).
- Treg Cytokines: IL-10 and TGF-β secreted by Tregs create an immunosuppressive barrier.
Conclusion
Tumours employ complex and overlapping strategies to evade immune responses. Understanding these tactics provides insight into cancer biology and therapeutic interventions, such as immune checkpoint inhibitors or strategies to reprogram the tumor microenvironment. By targeting these evasion mechanisms, researchers aim to restore immune system efficacy and improve cancer treatment outcomes.