L27: Cancer immunology Flashcards
Cancer
The progressive growth of the progeny of a single transformed cell. Transformation can be spontaneous or result of exposure to certain viruses, ionising radiation or mutagenic chemicals. Virtually all cancers are clonally derived from a single abnormal cell. Initiated by mutations in the cell’s DNA. Mutations can occur during DNA replication prior to cell division.
Immune surveillance theory
Proposes that the immune system continually surveys the body for the presence of abnormal cells which are destroyed when recognised. Also proposes that the immune system plays an important tole in the regression of established tumours
For IST
- Transplanted tumours usually regressed
- Spontaneous regression can occur
- Many tumours contain lymphoid infiltrates
- Tumours occur more frequently during neonatal period and old age
Against IST
- Cancer is too common
- Few tumours show evidence of immunological control
- Mice that lack lymphocytes show the same incidence of common tumours as those with intact immune systems
Immune surveillance
- When tumours arise in a tissue, a number of immune cells can recognise and eliminate them
- Variant tumour cells arise that are more resistant to being killed
- Over time a variety of different tumour variants develop
- Eventually one variant may escape the killing mechanism, or recruit regulatory cells to protect it so spread unchallenged
Growth patterns of transplantable tumours:
- Irradiated mice - transplanted tumours will grow
- Allogeneic mice - transplant tumours will be rejected
- Syngeneic mice - tumours may be progresses (grow unhindered) or regressors (grow initially, then rejected)
Tumour rejection antigens (TRAs)
- Found in normal cells but highly expressed in tumour cells
- Tumour-specific
- May be shared by tumours of a similar cellular origin
- Often oncofoetal proteins, activated by de-repression of preexisting genes
Evidence for tumour immunity
Adaptive immunity:
1. Ab and T cell responses to tumour antigens
2. Increased tumours in immunosuppressed patients and immune deficient animals
3. Effective antigen specific tumour immunotherapy
Innate immunity:
1. Total loss of MHC 1 unusual (NK surveillance)
Tumour facts (5)
- Have unique antigens (tumour specific antigens) that are neo-self
- Not presented well
- Immune surveillance prevents some tumours
- Tumours that slip through the net are poorly immunogenic but may be antigenic
- Can induce regulatory T cell responses that hinder effective immunotherapy
Antibody based immunotherapy - cell surface of interest (4)
- Idiotypes on T and B cell tumours
- Abnormally glycosylated proteins - MUC1 on Breast and other cancers
- Upregulated/mutated receptors - Her-2 Neu
- Inhibitory molecules on T cells - CTLA-4 and PD-1
Targeting toxic molecules/cells to tumour (3)
- Tumor-specific antibody: antibodies bind to the tumour cell, NK cells with Fc receptors (CD16) activated to kill tumour cells
- Tumour-specific antibody conjugated to toxin: antibody-toxin conjugates bind to tumour cell, conjugates are internalised, killing the cell
- Tumour-specific antibody conjugated to radionuclide: radioactive antibody binds to the tumour cell, radiation kills the tumour cell and neighbouring tumour cells
T cell immunotherapy
- Tumour virus proteins
- Mutated regulatory genes - new epitopes or new MHC binding capcity
- New antigens
- Normal proteins over-expressed to immunogenic levels
Mutated self antigens seen by T cells
Normal cell presents self peptides bound to MHC molecules:
- Point mutation in self protein allows binding of a new peptide to MHC molecule
- Point mutation in self peptide creates new epitope for recognition by T cells
Adoptive T cell immunotherapy
T cells which are infiltrating the tumour can be isolated, grown and then transplanted back into the patient
Targeting virus associated cancer (4)
- Prophylactic immunisation
- Therapeutic immunisation
- Virus specific siRNA therapy
- Virus protein specific small molecule inhibitors
