Immunological Aspects of Cancer

The immune system both protects against cancer development and can be exploited by tumours to escape immune destruction. Cancer can arise through several immune-related mechanisms: immunosuppression (e.g., transplant recipients on immunosuppressants have higher rates of lymphoma and skin cancers), infection with oncogenic viruses (e.g., HPV causing cervical cancer, HBV/HCV causing hepatocellular carcinoma, EBV causing Burkitt lymphoma), and chronic inflammation (e.g., H. pylori gastritis causing gastric cancer; chronic HBV/HCV hepatitis causing HCC).

Tumours are antigenically distinct from normal cells. They may over-express tumour-associated antigens (TAAs; e.g., PSA, HER2, survivin) from dysregulated gene expression, or express tumour-specific neoantigens (TSAs; e.g., bcr-abl in CML, EGFR mutations) resulting from genomic instability and somatic mutations. CD8 cytotoxic T cells can recognise neoantigen peptides on MHC class I and kill tumour cells, while NK cells kill cells that have downregulated MHC class I (a common immune evasion mechanism).

The immune response to cancer follows three phases: Elimination (immune system destroys cancer cells), Equilibrium (immune system and tumour co-exist in balance), and Escape (tumour cells that have evolved immune evasion mechanisms proliferate). Escape variants have often lost MHC class I expression, reduced expression of tumour antigens, upregulated immune checkpoint molecules (PD-L1), or recruited suppressive immune cells (myeloid-derived suppressor cells, tumour-associated macrophages).

Immunotherapy exploits these mechanisms therapeutically. Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1/PD-L1) block molecules that cause T-cell exhaustion, reinvigorating anti-tumour immune responses; effects persist even after drug withdrawal. Chimeric antigen receptor (CAR) T-cell therapy involves engineering patient T cells with an antibody-based receptor against a tumour antigen (e.g., anti-CD19 for lymphoma) and re-infusing them. Adoptive transfer of tumour-infiltrating lymphocytes (TILs) amplified ex vivo represents another approach. Chemotherapy can also be immunogenic, causing immunogenic cell death that alerts and activates the immune system against the tumour.