Tumour Immunology Flashcards
Cancer and the immune system
- Many tumours do not get detected by the immune system
- The reasons why are:
1. Cancers are not infectious agents so they do not have PAMPs (pathogen-associated molecular patterns) that allow the immune system to be aware of a problem
2. Cancers are derived from normal cells (self) and our body is trained to be tolerant to normal cells, so autoimmune reactions don’t occur.
Lack of T-cell costimulation results in tolerance to tumour antigens
- Tumour cells are derived from normal cells, so they do not have non-self determinants
- Another problem is that adaptive immune cells do not usually enter tissues unless thy have been recruited by innate cells as a result of PAMP-initiated inflammatory response. As cancer cells lack PAMPs, the innate cells bind them, and consequently cannot recruit the adaptive immune cells to the tissues. Therefore, even a if a mutation has caused the expression of molecules that would not normally be expressed in the body (non-self), it won’t cause an adaptive immune response unless it is costimulated. Dendritic cells in the tissues are immature and do not migrate to lymph nodes to present antigen unless activated by a PAMP or another source of recognition receptor-stimulation such as DAMP (danger-associated molecular pattern, which is a structure or molecule produced by necrotic cells and which provides danger signals to activate the immune response following tissue damage). Therefore, a tumour neoantigen will be ignored by the immune system unless presented by a mature dendritic cell so tolerization to the tumour antigen will occur - this occurs passively. However, tumours deliberately induce tolerance by secreting factors such as IL-10 and VEGF to make nearby dendritic cells tolerant. Tumours also secrete other factors like TGF-beta to suppress T-cell activation, proliferation and differentiation which is known as activer tolerization.
Inflammation and cancer
- Tumours often contain many tumour-associated macrophages and neutrophils but the tumours have recruited them to help tumour cells proliferate and progress
- Tumours secrete inflammatory cytokines and chemokines (IL-1, IL-6, IL-8) - inflammation drives tumour growth
- These inflammatory mediators recruit neutrophils and macrophages which produce cytokines and promote proliferation/growth of the tumour, and angiogenesis that are required for rapidly growing cells
- The tumour associated inflammatory cells, especially macrophages produce reactive oxygen and nitrogen species, resulting in DNA mutations that drive metastasis and progression
- Macrophage density correlates with a poor prognosis in 80% of cancers
- Tumours produce anti-inflammatory cytokines (IL-10, TGF-beta) so tumours manipulate the immune cells so that they benefit from them rather than being detected by them. Sometimes immune responses can remove the tumours
- Tumours which produce an inflammatory environment can be treated with neutralising antibodies against the cytokines driving tumour growth and angiogenesis, or by giving the patients anti-inflammatory drugs
Tumour antigens
- Tumour antigens derive from normal proteins to which the immune system is not tolerant and become immunogenic when expressed by the tumour. Immune responses to tumours do occur, but they are modest - this is partly due to evasiveness of tumours as a result of their genomic instability, but also due to an acquired state of immune tolerance to the tumour.
- For the immune system to mount an effective antitumour response, the tumour must express molecules that are not normally found within the body or fail to express molecules that are not normall present on healthy cells
- MHC class I molecules are are displayed on the surface of all nucleated cells - however, failure to express MHC molecules is one of the criteria NK cells use to select target cells for attack.
Viral antigens
- Some tumours develop as a result of oncogenic viral infection - EBV in lymphomas, human T-cell leukaemia virsu 1 (HTLV1) in leukaemia and HPV in cervical cancers.
- After infection, the viruses express genes homologous to cellular oncogenes which encode factors affecting growth and cell division. Expression of these genes therefore leads to potentially malignant transformation.
- All tumours induced by a given virus should carry the same surface antigen (tumours induced by a given virus should carry the same surface antigen (tumours induced by oncogenic viruses have processed viral peptides on the surface of all neoplastic cells bearing the viral genome.
Expression of normally silent genes
-Sometimes, these encode differentiation antigens that are normally associated with an earlier developmental stage. Oncofetal antigens are antigens that are found on embryonic cells and on tumour cells.
- MAGE-1 is not expressed in normal tissue except for germline cells in testes, so when this is expressed it indicates presence of a tumour
Mutant antigens
- Mutated peptides have been identified in human tumours.
- For example, the gene encoding the cell cycle checkpoint protein p53 is a hotspot for mutations in numerous cancers. The mutated forms of p53 are inactivating or loss of function mutations, that fail to arrest division of cells that have suffered enough DNA damage and which would normally cause cell cycle arrest or apoptosis of the cell.
- RAS mutations are normally point mutations usually causing single amino acid substitution in codons 12, 13 and 61. These mutations generate constitutively active forms of RAS that promote increased rates of cell division through the MAPK pathway.
Changes in carbohydrate on cell surface
Cancers often present abnormal carbohydrate structure on the cell surface which can affect the metastatic potential of the tumour
Tumour antigenicity
Tumours are derived from our own cells, so it is expected that the body would produce an immune response against our own cells (tolerance). Tumours can be antigenic for many reasons:
1. Mutations - if a mutation results in a novel peptide being generated, the tumour may become immunogenic
2. Oncofetal antigens - some tumours re-express molecules that are normally found in the foetus (oncofetal antigens). Immunological tolerance requires a continuous supply of antigen being available to the immune system. New T-cells are being formed continuously and can only be tolerized if they see antigen.
3. Some tumours are induced by viruses - if the viral genome is incorporated into the host genome, viral proteins can be made which are foreign peptides
4. We are not tolerant to all cellular proteins - some are present in too small amount to induce tolerance. However, if expressed in large amounts by tumours, they can cause an immune response.
Immunopriveliged sites: cancer/testis (CT) antigens
- Sites with immune privilege are anatomical regions that are naturally less subject to immune responses than most areas of the body. For example, the central nervous system, brain, eyes and testis
Tumour Immunology Cycle
- Tumours are characterised by mutations that lead to neoantigens specific to the tumour; some tumours (HPV+) express unique viral antigens that set tumours apart from normal tissue
- Dendritic cells present tumour antigens to T-cells; if all goes well, the T-cell will be activated and return to the tumour to kill tumour cells based on recognition of tumour-specfiic neoantigens or viral antigens
- However, tumours are smart and have figured out ways to escape the immune system or to turn off immune response
What is a neoantigen?
Antigens that may be frequently associated with tumours or may be specifically found on tumour cells of the same antigen (tumour specific), tumour antigens may also be associated with replication and transformation by certain DNA tumour viruses, including adenoviruses and papoviruses.
What is a dendritic cell?
Accessory (antigen presenting) cells, positive for class II histocompatibility antigens, found in the red and white pulp of the spleen and lymph node cortex and associated with stimulating T-cell proliferation
Tumour immunosurveillance
Immune surveillance is the theory that the immune system patrols the body to not only recognise and destroy invading pathogens, but also host cells that become cancerous. Perhaps potential cancer cells arise frequently through life, but the immune system destroys them as fast as they appear. Tumour cells undergo clonal evolution by acquiring mutations to evade detection.
Immune surveillance
For immune surveillance to work, cancer cells need to express antigens that are not found on normal cells. Otherwise, the immune system would see them as ‘self’ and be tolerant of them.
Some examples of tumour antigens (antigens expressed by cells infected with oncogenic viruses):
- HPV: risk factor for cervical cancer
- KSHV: the virus that causes Kaposi’s sarcoma
- EBV: predisposes to Burkitt’s lymphoma
- Hepatitis B: predisposes to liver cancer
Host gene products that are overexpressed or expressed in inappropriate cells:
- MAGE-A3
- NY-ES01: a protein that is produced by by several types of tumours (melanoma, lung cancer) but not by normal tissue expect from tissue in the testes as it is immunologically priveliged site
- Human Epidermal Growth Factor Receptors (HER2): a growth factor receptor found on some tumour cells (some breast cancers)
Host gene products that are structuraly altered by somatic mutation:
- A mutated version of the gene (IDH1) encoding the protein isocitrate dehydrogenase type 1 is frequently found in several types of cancer. In mice, a vaccine presenting a peptide including the mutant sequence elicits a Th-1 cell response that slows tumour growth
- A mutated version of a protein that binds with HER2 expressed in a carcinoma is recognised by the patient tumour infiltrating lymphocytes (TILs) and these Th1 cells can destroy the tumour cells
