Tumour Immune Evasion
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Direct answer
Cancers that survive the immune system have passed through immunoediting — elimination, in which innate and adaptive immunity destroy transformed cells; equilibrium, in which residual variants are held in check under selective pressure; and escape, in which edited tumour cells with immune-evasive traits grow clinically. Evasion itself is a toolkit: loss or alteration of major histocompatibility complex (MHC) class I so cytotoxic T cells cannot see the tumour, expression of inhibitory checkpoint ligands such as programmed death-ligand 1 (PD-L1) that switch off T cells, recruitment of regulatory T cells and tumour-associated macrophages, secretion of immunosuppressive cytokines like transforming growth factor-beta and interleukin-10, and induction of T-cell exhaustion. Modern immunotherapy is simply the reversal of these mechanisms — checkpoint inhibitors releasing the brakes that tumours have learned to pull.
What you must remember
- Immunoediting phases: elimination (immune surveillance wins), equilibrium (editing under pressure; the longest phase), escape (clinical cancer) — the framework that explains why cancers appearing years after transplantation follow immunosuppression.
- Antigen invisibility: downregulation or total loss of MHC class I (including beta-2 microglobulin mutations that abolish expression) hides tumour peptides from CD8 T cells; natural killer cells then matter, because "missing self" is their activating signal — the tumour trades T-cell attack for NK vulnerability.
- Checkpoint co-option: PD-L1 on tumour cells (or on infiltrating myeloid cells) ligates PD-1 on activated T cells, delivering an inhibitory signal that causes exhaustion; cytotoxic T-lymphocyte antigen-4 (CTLA-4) on T cells outcompetes CD28 for B7 on antigen-presenting cells — these are the two brakes targeted by pembrolizumab/nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4).
- Regulatory cells: FOXP3-positive regulatory T cells and M2-polarised tumour-associated macrophages suppress effector responses inside the tumour; depleting or re-polarising them is an active therapeutic strategy.
- Cytokine shield: transforming growth factor-beta and interleukin-10 from tumour and stromal cells suppress cytotoxicity and promote fibrosis; vascular endothelial growth factor further blocks dendritic-cell maturation.
- Antigen loss and immune ignorance: tumours delete the very antigens that drew the original attack (antigen-loss variants), hide behind stromal barriers, or exploit low co-stimulation to induce anergy rather than immunity.
- Oncovirus angle for India: Epstein-Barr virus, human papillomavirus and hepatitis B virus cancers carry viral antigens — the reason hepatitis B vaccination prevents hepatocellular carcinoma and HPV vaccination (now in India's immunisation schedule for adolescent girls) prevents cervical cancer.
- Tumour mutational burden: highly mutated cancers (melanoma, smoking-associated lung cancer, mismatch-repair-deficient tumours) present more neoantigens and respond better to checkpoint blockade — why microsatellite-instability testing precedes immunotherapy selection.
A worked example: why the checkpoint question works
Take a metastatic melanoma that progressed after targeted therapy. Its cells carry hundreds of mutations, so neoantigens abound on MHC class I — yet the tumour grows, because intra-tumoural T cells stain positive for PD-1 and the tumour for PD-L1: exhausted lymphocytes, brakes fully engaged. Infuse a PD-1 antibody and the brake is released; pre-existing T cells re-attack, and responses can be durable for years. Now run the counter-case: a microsatellite-stable pancreatic cancer with few neoantigens, sparse T-cell infiltrate ("cold" tumour), dense transforming growth factor-beta stroma — checkpoint blockade alone fails because there is no army to unleash; the answer must combine chemoactivation of antigens, stromal targeting or adoptive cell therapy. The same logic explains toxicities: releasing brakes systemically unleashes immunity against normal tissues — colitis, thyroiditis, pneumonitis — and the pathologist recognising immune-related adverse effects is part of modern practice.
Where students slip
The first confusion is equating "immune surveillance" with an always-vigilant system that cancers simply overwhelm; the edited-tumour concept says the survivor is actively shaped by immune selection — which is why cancers in immunosuppressed transplant recipients are disproportionately virus-associated and antigen-rich. The second slip is misplacing PD-L1: it is the ligand on tumour and myeloid cells, PD-1 the receptor on T cells — reversing them in a viva undermines the whole mechanism answer. The third is forgetting NK cells when MHC is lost: students end the story at "tumour hides from CD8 cells," whereas "missing-self" recognition is precisely the immune system's counter-move, and tumours that lose MHC must also develop NK resistance.
Frequently asked questions
What are the three phases of cancer immunoediting?
Elimination, in which the immune system destroys transformed cells; equilibrium, a dynamic stalemate that edits tumour variants; and escape, when surviving cells grow into clinical cancer.
How does PD-L1 help a tumour evade immunity?
PD-L1 on tumour or myeloid cells engages PD-1 on activated T cells, transmitting an inhibitory signal that exhausts them — blocked therapeutically by anti-PD-1 or anti-PD-L1 antibodies.
Why do MHC class I-negative tumours fear NK cells?
Natural killer cells are activated by the absence of self MHC class I ("missing-self" recognition), so tumours hiding from cytotoxic T cells become NK targets.
Which cell types suppress anti-tumour immunity inside a tumour?
FOXP3-positive regulatory T cells, M2-polarised tumour-associated macrophages and myeloid-derived suppressor cells, together with TGF-beta and IL-10-secreting stroma.
Why do mismatch-repair-deficient cancers respond well to checkpoint inhibitors?
High mutational burden generates abundant neoantigens for T-cell recognition, so releasing checkpoints produces vigorous, clinically meaningful anti-tumour responses.