Lecture 7 - Tumour Immunity I Flashcards
Does the immune system recognise tumours?
Tumour cells are derived from self tissue
There is a question as to whether they are sufficiently different to be recognised
However, there is evidence that they are in fact sufficiently different
Evidence:
• Lymphocyte infiltrate in tumour correlates to better prognosis
• Tumours are more common in immunosuppressed individuals
List some of the ways that the immune system can control cancer
1. Immune control of tumourogenic infections • EBV • Kaposi Sarcoma virus • HPV • HBV, HCV
- Abs as immunotherapy for cancer
3. Targeting of tumour cells: • B cells • 'helper' T cells • CTLs • NK cells • NKT cells
Describe immune control of tumourogenic viruses through an illustrative example
Certain viruses cause cancer:
• EBV especially
e.g. EBV
1. T cell control
• CTLs specific for EBV Ags recognised infected B cells and kill them (perforin and granzyme dependent killing)
• ‘Helper’ T cells stimulate B cell responses against EBV
- B cell control
• B cells generate Ab against extracellular virus particles
Describe EBV infections
EBV latently infects B cells
Infection is widespread in humans
Causes glandular fever / mononucleosis
Infection is normally controlled by the immune system
EBV can cause lymphoma, often when individual is immunosuppressed
Describe EBV in immunosuppressed individuals
Immunosuppression due to:
• AIDS
• Innate defect
• Malaria
Infected B cells are not killed off by CTLs
Virus is able to replicate and infect many B cells, causing B cell proliferation
Chance chromosomal translocation causes B cells to proliferate in an uncontrolled manner
Which cancer does EBV sometimes cause?
Lymphoma
Burkitt’s lymphoma
Which cancer does HPV cause?
Cervical cancer
Which cancer do HCV and HBV cause?
Hepatocellular carcinoma
What is the correlation between immunosuppression and cancer?
Immunosuppression increases risk of cancer
Particularly: • Kaposi sarcoma • Non-Hodgkin lymphoma • Liver carcinoma • Skin carcinoma
Describe the evidence for existence of tumour Ags
One can vaccinate mice against tumours
Process:
1. Mice injected with irradiated tumour cells (i.e. unable to cause tumour)
2a. Some mice then injected with viable tumour cells of the same tumour
3a. Mouse does not develop a tumour
2b. Other mice injected with viable tumour cells from a different tumour
3b. Mouse develops a tumour
Give an overview of the various tumour Ags
– Mutated –
- Products of mutated genes
• Oncogenes
• e.g. p53, Rab, Bcr/abl - Products of oncogenic viruses
• e.g. E6 & E7 in HPV infection
• EBNA-1 in EBV infection - Altered forms / levels of glycolipid / glycoprotein Ags
• e.g. MUC-1 glycoprotein in breast carcinoma
– Unmutated –
- Aberrantly expressed Ags
• e.g. Oncofoetal Ags
• Normally only expressed in the foetal colon
• Expressed in adult colon cancer - Tissue specific differentiation Ags
• e.g. CD20 on B cells
Describe how altered levels of Ags in tumours can be a target for the immune system
Tumour cells often over-express normal self proteins
This increases the density of presentation of this peptide
The density now exceeds the threshold required to activate T cells
Describe the role of the various lymphocytes against tumours
– T cells –
- CTLs
• Directly kill tumours presenting tumour Ag in MHC I
2. 'helper' T cells • Help CTL responses • Help B cell responses • Produce cytokines (IFN-gamma, IL-2) • Produce tumouricidal cytokines (TNF, LT)
– B cells –
Produce Abs against tumour Ags:
- ADCC
• Abs bind to surface of tumour cells
• NK cells and macrophages bind Ab through their FcRs
• NK cells kill tumour cell through perforin and granzyme dependent killing - C’ dependent cellular cytotoxicity
Describe NK cell action against tumour cells
Tumour cells may:
1. Upregulate ‘Stress’ markers: MIC-A
NK cells recognise stress markers on the surface of tumour cells through NKG2D
Ligation go NKG2D can override inhibitory signals delivered through KIR by MHC on the tumour cells
NK cells become activated and kill tumour cells with perforin and granzymes
- Down regulate MHC
When MHC is down-regulated, NK cells do not receive the inhibitory signals through KIR
NK cells become activated and kill the tumour cells
Describe the features of NKT cells
• Cell surface markers
• Function
Express:
• α/β TCR; invariant
• NK1.1
They have features of both NK and T cells
TCR recognises glycolipid and lipid presented in the context of CD1d
Function: • Strong producer of cytokines: IFN-gamma, IL-4, TNF) • Provide help for NK and T cells • Enhance DC maturation and activation • Perforin-dependent killing of cells
Describe the role of NKT cells against tumours
- Tumour cell presenting tumour glycolipid Ag in the context of CD1d
- NKT cells recognise tumour Ag with (invariant) TCR and become activated
- NKT cells produce cytokines:
• IFN-gamma
( • TNF
• IL-4) - IFN-gamma helps DCs and CTLs
Outcome:
• Enhanced CTL responses against tumour
List the different mechanism of tumour escape of the immune system
- Low immunogenicity
- Tumour treated as self Ag
- Antigen modulation
- Tumour-induced immune suppression
- Isolation
Describe how ‘Low immunogenicity’ can mean tumour escape
Tumour cells do not express:
• MHC:peptide complexes
• Co-stimulatory molecules
• Adhesion molecules
T cells can not recognise the tumour cells
Describe how tumours can be treated as self-antigen
DCs take up Ag from tumour cells, but do not express co-stimulatory molecules
When T cells see the tumour Ag presented by the DCs, in the absence of co-stimulation, there is a ‘tolerising’ response
Describe how antigenic modulation can lead to tumour escape
Tumour cells are rapidly proliferating and are genetically unstable
Loss of Ag through:
• Mutation
• Mutants have a selective advantage
Is loss of MHC I a feature of cancer?
Some cancers, yes
It is very common in colon cancer
This allows them to evade CTL responses
If all MHC I molecules are lost, the tumour cells are a target for NK cells
If they lose only some MHC I, they may escape both CTL and NK cell responses
Describe the mechanism of tumour induced immunosuppression
Tumours secrete immunosuppressive cytokines:
• IL-10
• TGF-beta
These inhibit lymphocyte function and Ag presentation
Describe the role of Tregs in tumour immunity
Treg infiltrates in tumours are common and correspond to poorer prognosis
Tregs produce immunosuppressive cytokines that suppress NK cells and CTLs
Elimination of Tregs can promote tumour rejection
Describe how tumours can induce an immune privileged site
Tumours can generate a barrier than prevents immune cells from accessing the tumour Ags
Tumour cells are … unstable
Genetically
Describe the three Es of tumourigenesis
Elimination:
• When tumour cells arise, the immune system recognises them and kills them off
Equilibrium:
• Tumour cells that are not recognised by the immune system are selected
Escape:
• Eventually, one variant may escape the killing mechanism & recruit Tregs
• It can proliferate unchallenged
Describe a case that provides evidence for the latency / equilibrium phase of cancer
Individual donated kidneys to two individuals upon death
Donor had had primary melanoma 16 years previously
Both recipients developed metastatic melanoma after transplant, as they were immunosuppressed
Implication:
• Melanoma was latent in the donor for those 16 years, but controlled by the immune system
• When these tumour cells were transplanted into immunosuppressed individuals, the tumour cells could grow unchecked
What are MAGE and MART?
Ags that are expressed in melanomas
These ags are not normally expressed in adult tissues
They are also expressed in the testes, hence the name C/T Ags (Cancer testes ags)
What are E6 and E7?
Ags from HPV(16)
These are examples of tumour antigens from oncogenic viruses
What is CEA?
Carcinoembryonic antigen (aka oncofoetal antigen)
An example of aberrantly expressed self-ags in cancer
These Ags are normally only expressed in the foetus, but is expressed in colorectal cancer
Give examples of altered glycolipid and glycoprotein Ags in tumours
MUC-1 glycoprotein - expressed by breast carcinoma
GM2 & GD3 glycolipids - expressed in melanoma
Give examples of tumour Ags that are the products of oncogenic viruses
E6 & E7 of HPV
EBNA-1 of EBV
Give examples of tumour Ags that are products of mutated genes
Ras
Bcr/abl
p53
