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MIIM30003 - Medical & Applied Immunology > Lecture 7 - Tumour Immunity I > Flashcards

Lecture 7 - Tumour Immunity I Flashcards

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USMLE® Step 1 flashcards
1
Q

Does the immune system recognise tumours?

A

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

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2
Q

List some of the ways that the immune system can control cancer

A 
1. Immune control of tumourogenic infections
 • EBV
 • Kaposi Sarcoma virus
 • HPV
 • HBV, HCV
  1. Abs as immunotherapy for cancer
3. Targeting of tumour cells:
 • B cells
 • 'helper' T cells
 • CTLs
 • NK cells
 • NKT cells
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3
Q

Describe immune control of tumourogenic viruses through an illustrative example

A

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

  1. B cell control
    • B cells generate Ab against extracellular virus particles
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4
Q

Describe EBV infections

A

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

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5
Q

Describe EBV in immunosuppressed individuals

A

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

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6
Q

Which cancer does EBV sometimes cause?

A

Lymphoma

Burkitt’s lymphoma

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7
Q

Which cancer does HPV cause?

A

Cervical cancer

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8
Q

Which cancer do HCV and HBV cause?

A

Hepatocellular carcinoma

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9
Q

What is the correlation between immunosuppression and cancer?

A

Immunosuppression increases risk of cancer

Particularly:
 • Kaposi sarcoma
 • Non-Hodgkin lymphoma
 • Liver carcinoma
 • Skin carcinoma
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10
Q

Describe the evidence for existence of tumour Ags

A

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

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11
Q

Give an overview of the various tumour Ags

A

– Mutated –

  1. Products of mutated genes
    • Oncogenes
    • e.g. p53, Rab, Bcr/abl
  2. Products of oncogenic viruses
    • e.g. E6 & E7 in HPV infection
    • EBNA-1 in EBV infection
  3. Altered forms / levels of glycolipid / glycoprotein Ags
    • e.g. MUC-1 glycoprotein in breast carcinoma

– Unmutated –

  1. Aberrantly expressed Ags
    • e.g. Oncofoetal Ags
    • Normally only expressed in the foetal colon
    • Expressed in adult colon cancer
  2. Tissue specific differentiation Ags
    • e.g. CD20 on B cells
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12
Q

Describe how altered levels of Ags in tumours can be a target for the immune system

A

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

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13
Q

Describe the role of the various lymphocytes against tumours

A

– T cells –

  1. 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:

  1. 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
  2. C’ dependent cellular cytotoxicity
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14
Q

Describe NK cell action against tumour cells

A

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

  1. 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

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15
Q

Describe the features of NKT cells
• Cell surface markers
• Function

A

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
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16
Q

Describe the role of NKT cells against tumours

A
  1. Tumour cell presenting tumour glycolipid Ag in the context of CD1d
  2. NKT cells recognise tumour Ag with (invariant) TCR and become activated
  3. NKT cells produce cytokines:
    • IFN-gamma
    ( • TNF
    • IL-4)
  4. IFN-gamma helps DCs and CTLs

Outcome:
• Enhanced CTL responses against tumour

17
Q

List the different mechanism of tumour escape of the immune system

A
  1. Low immunogenicity
  2. Tumour treated as self Ag
  3. Antigen modulation
  4. Tumour-induced immune suppression
  5. Isolation
18
Q

Describe how ‘Low immunogenicity’ can mean tumour escape

A

Tumour cells do not express:
• MHC:peptide complexes
• Co-stimulatory molecules
• Adhesion molecules

T cells can not recognise the tumour cells

19
Q

Describe how tumours can be treated as self-antigen

A

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

20
Q

Describe how antigenic modulation can lead to tumour escape

A

Tumour cells are rapidly proliferating and are genetically unstable

Loss of Ag through:
• Mutation
• Mutants have a selective advantage

21
Q

Is loss of MHC I a feature of cancer?

A

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

22
Q

Describe the mechanism of tumour induced immunosuppression

A

Tumours secrete immunosuppressive cytokines:
• IL-10
• TGF-beta

These inhibit lymphocyte function and Ag presentation

23
Q

Describe the role of Tregs in tumour immunity

A

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

24
Q

Describe how tumours can induce an immune privileged site

A

Tumours can generate a barrier than prevents immune cells from accessing the tumour Ags

25
Q

Tumour cells are … unstable

A

Genetically

26
Q

Describe the three Es of tumourigenesis

A

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

27
Q

Describe a case that provides evidence for the latency / equilibrium phase of cancer

A

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

28
Q

What are MAGE and MART?

A

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)

29
Q

What are E6 and E7?

A

Ags from HPV(16)

These are examples of tumour antigens from oncogenic viruses

30
Q

What is CEA?

A

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

31
Q

Give examples of altered glycolipid and glycoprotein Ags in tumours

A

MUC-1 glycoprotein - expressed by breast carcinoma

GM2 & GD3 glycolipids - expressed in melanoma

32
Q

Give examples of tumour Ags that are the products of oncogenic viruses

A

E6 & E7 of HPV

EBNA-1 of EBV

33
Q

Give examples of tumour Ags that are products of mutated genes

A

Ras
Bcr/abl
p53

MIIM30003 - Medical & Applied Immunology (30 decks)

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