Tumour antigens are protein, glycoprotein or glycolipid sequences produced by tumour cells. An antigen in this setting is a cytoplasmic peptide which can be targeted by the immune system or by targeted therapy.
For immune system recognition, antigens are presented on the cell surface by the MHC 1 complex (important for cytotoxic T-lymphocytes CD8+), or alternatively phagocytosed proteins may be presented to CD4+ helper T-lymphocytes.
Mutated gene products
If a mutation leads to a novel protein product, then the protein may be recognised as ‘non-self’ when presented on an MHC 1 molecule to a CD8+ cell.. This includes mutations in TP53 or RAS. Mutated proteins from dead tumour cells may be phagocytosed and then presented to CD4+ T-helper cells.
Overexpressed normal gene products
Normal genes may be overexpressed in some tumours. This overexpression may lead to an immune response, but typically only when the involved gene is usually minimally expressed or only expressed in non-MHC presenting cells (eg. spermatozoa). Melanoma typically expresses high levels of tyrosinase, an enzyme only found in normal melanocytes. This low level of expression explains why many immune systems do not recognise the tyrosinase molecule as ‘self’.
Ongogenic viral proteins
Viral proteins which induce carcinogenesis may also induce an immune response against the infected cell. CD8+ T-lymphocytes seem to be have a critical role in detection of these tumour antigens.
Oncofoetal proteins are only expressed during foetal development and in malignancies. They may have a role in tumour growth. The most well known oncofoetal proteins are carcinoembryonic antigen (CEA) and alpha-foetoprotein (αFP). The oncofoetal proteins are noted for their use as tumour markers.
Altered non-protein surface molecules
Tumour cells may express a different complement of cellular glycoslated proteins and lipids. These may be recognised by the immune system as an abnormality.
Antigens from cell of origin
As opposed to the other types of antigens, these antigens are normally produced by cells from which the cancer arose. If the cancer retains these normal proteins, then they may be used as a target for therapy (eg. CD20 in lymphoma). These antigens do not normally induce an immune response.
Antitumour Effector Mechanisms
There are four primary methods by which the immune system responds to tumour cells:
- Cytotoxic T-lymphocytes react against tumour cells that express MHC 1 molecules. The MHC 1 molecule must present the antigen to the CTL for recognition, which then leads to activation of apoptosis in the abberant cell.
- Natural killer cells (CD4- CD8-) are activated by a different pathway, and the presence of MHC 1 molecules reduces their activation. They may work in concert with CTLs by targeting tumour cells with reduced MHC expression
- Macrophages phagocytose tumour cells and release tumour necrosis factor, leading to cell death.
- Antibodies may be produced against tumour antigens. This is uncommon in spontaneous tumour development, but monoclonal antibodies administered to a patient may lead to therapeutic benefit (eg. CD20 in B-cell lymphoma).
Immune Surveillance and Escape
Immunodeficiency (congenital or acquired) is known to increase the development of tumours. It is also known that there are various immune pathways which are able to sense and destroy tumour cells. It therefore follows that to develop, tumours must be able to evade detection or destruction by the immune system.
There are several proposed mechanisms for escaping immune surveillance:
- Elimination of immunogenic clones leading to growth of less immunogenic tumour clonagens
- Failure of expression of MHC I molecules (may trigger NK activation)
- Failure of expression of co-stimulatory molecules required for CD8+ T-cell activation
- Immunosuppression may lead to inability to combat tumour cells. Tumours may produce their own immunosuppressents which prevent normal immune system response.
- Antigen masking by additional glycocalyx molecules, frequently produced by tumour cells to excess.
- Induction of apoptosis in T-lymphocytes which contact the tumour.
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