Tumour Antigens

Tumour antigens are the antigenic substances produced by tumour cells that trigger immune response in the host. The immune system recognises tumour antigens as foreign substances or nonself systems. Current research involves investigation of immunogenomics biomarkers related to tumour antigens.

Neoantigens

Neoantigens are antigens that are newly formed from altered tumour proteins. Although neoantigens are new to the immune system, they can induce immune response, and these antigens may help to predict sensitivity of tumours to immuno-oncology therapy.

Importance

  • Neoantigens are antigens that are newly formed and also new to the immune system.
  • Neoantigens are formed from altered tumour proteins that are produced as a result of tumour mutation.
  • Conditions of high neoantigen production include: high tumour mutational burden (TMB), microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR) status, or MGMT methylation.
  • The immune system recognises neoantigens as foreign substances or nonself system.
  • T cells with high specificity towards neoantigens have been reported in several human cancers.
  • The presence of high neoantigen burden on certain tumours makes them more sensitive to immunotherapy. This implies that neoantigens can be therapeutic target and potential immunogenomics biomarker.

Tumour Mutational Burden (TMB)

TMB is the quantitative amount of mutations present in the tumour genome. It serves as a predictive biomarker for predicting the effectiveness of immune-oncotherapies in different patients.

Importance

  • TMB is defined as the number of non-synonymous, somatic mutations in the tumour genome.
  • High mutational burden in tumours is correlated with a high expression of neoantigens.
  • High TMB leads to increased infiltration of cytotoxic T cells into the tumour microenvironment.
  • Neoantigens can elicit anti-tumour immune response, and thus increasing the immunogenicity of the tumour.
  • DNA mutation through dMMR, exposure to environmental mutagens (e.g., tobacco smoke and UV light), carcinogens (harmful chemicals e.g., such as asbestos and benzene) can increase high TMB.

MSI-H/dMMR

Microsatellite instability (MSI) is said to be present if nucleotide repeats in tumour and normal healthy tissue differs. It is a result of deficient mismatch repair (dMMR) that causes the inability to inability to correct DNA replication errors leading to genomic instability

High level of neoantigen expression is found in MSI-H/dMMR tumours.

Importance

  • MSI: The number of nucleotide repeats in DNA sequences gets altered compared to normal healthy cells. Inability to rectify this DNA replication error can increase the risk of cancer. A tumour displaying high MSI (MSI-H) is reported to have at least 2 unstable markers out of the 5 microsatellite markers analysed (or approximately >30% of the microsatellite markers if a larger panel is analysed).
  • dMMR: DNA mismatch repair (MMR) is a prominent and highly conserved DNA repair pathway that relies on the MMR protein complex for its functioning. dMMR represents a loss of functionality of the MMR pathway.
  • Neoantigen expression increases with increase in MSI/dMMR.
  • Both tumours with high TMB and those with high MSI have high neoantigen expression. However, not all high-TMB tumours are MSI-H. Thus, MSI is not an appropriate surrogate marker for TMB.