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CAN > L18: Tumour Immunology > Flashcards

L18: Tumour Immunology Flashcards

1
Q

Which mouse study proves that tumours are immunogenic

A

1) inject a carcinogen to a mouse
2) this causes a tumour in that mouse
3) take the live tumour cells and grow it in a lab
4) give the tumour cell to a different mouse and the mouse will also develop a tumour
5) if you irradiate the tumour cell so they cannot divide and vaccinate to another mouse and then give the live tumour cell the mouse will remain tumour free

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2
Q

Describe the mouse experiment that shows tumours can induce immunological memory

A

1) inject a carcinogen to a mouse
2) mouse develops cancer
3) surgically respect the tumour and collect the tumour cell
4) if you give the tumour cell to a different mouse it will grow a tumour
5) if you give the tumour cell back to the original mouse the mouse will remain tumour free

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3
Q

In mouse experiments is tumour protection seen in mouse with T cell deficiency

A

No

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4
Q

If we do not have protection against tumour when there is T cell deficiency what does this indicate

A

That T cell plays a key role in protecting cancer

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5
Q

What is the concept of immunosurvelliance

A

The immune system recognises precursors of cancer and destroys the precursor of cancer before they become clinically apparent

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6
Q

What is the concept of cancer immunoediting

A

Immune system edits the immunogenicity of tumours that may form

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7
Q

What are the 3 Es of cancer immunoediting

A

Elimination
Equilibrium
Escape

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8
Q

What is elimination

A

Immune mediated destruction of cancer cells

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9
Q

What is equilibrium

A

Immune system is able to control the outgrowth of tumours but cannot eliminate the tumour cells

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10
Q

What is escape

A

Tumour mutated variant forms is no longer controlled by the immune system as the cells selected in the equilibrium phase grow out

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11
Q

What MHC complex doeS CD8 T cells detect

A

MHC1

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12
Q

What MHC complex does CD4 T cells detect

A

MHC2 complex

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13
Q

Where can MHC complex be found

A

Antigen presenting cells i.e tumour cells

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14
Q

What does the MHC complex bind to

A

T cell receptor

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15
Q

When the MHC complex binds to a T cell receptor what happens

A

A signal is delivered to the T cell so it becomes activated = signal 1

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16
Q

After signal 1 one what signal occurs

A

Signal 2

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17
Q

How does the T cells receive signal 2

A

CD80/CD86 on APC binds to CD28 on T cells

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18
Q

What can signal 2 be like

A

Positive co-stimulation

Negative co-stimulation

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19
Q

Give an example of positive co-stimulation in signal 2

A

CD80/CD86 binding to CD28 on T cell

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20
Q

Give examples of negative co-stimulation

A
  • CD80/CD86 binds to CTLA-4 (on T cell)

- PDL1/2 bins to PD-1 (on T cell)

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21
Q

What does the positive co-stimulation do

A

Activate the T cell

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22
Q

What does the negative co-stimulation do to the T cell

A

Suppress

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23
Q

Does CD28 or CTLA-4 binds strongly to CD80/CD86

A

CTLA-4

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24
Q

Overall what regulates the activity of T cells

A

Both positive and negative co-stimulation

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25
Q

If a T cell can recognise a tumour antigen describe how it will occur

A

1) tumour antigens are released
2) antigen is picked up by dendritic cells
3) dendritic cells drains to lymph nodes
4) dendritic cells present the antigen to T cells
5) if one of the T cells have appropriate receptor for the antigen, the T cell will clonal expand
6) T cells will leave lymph node into the blood to reach tumour site and destroy it

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26
Q

What are the tumour associated antigens that can be present for a T cell to recognise

A

Mutated self proteins generated by dna damage
Overexpressed self proteins
Lineage specific antigens
Abnormal post translational modification of self protein
Viral proteins
Antigens in the tumour stroma

27
Q

What does the tumour have to be like so we can target it with immunotherapy

A

Tumour specific : so we don’t destroy health cells
Antigen shared amongst different tumour : so we can target many cancer
Critical for tumour growth
Antigen to which immune system is not tolerant

28
Q

What are the 2 types of immune tolerance

A

Central tolerance

Peripheral tolerance

29
Q

What is the central tolerance

A

In the thymus when positive selection (binding to MHC complex) and negative selection (binding to self antigen) occurs

30
Q

What is peripheral tolerance

A

When any auto reactive T cell that escapes the thymus will be inactive when it interacts with self proteins

31
Q

Why is tolerance important

A

Cancer develops from our own tumour cels so immune system will be tolerant to it, if a antigen that you are not tolerant to occurs then you can destroy the cell

32
Q

Normally how does a cell process MHC class 1

A

1) proteins are synthesised in the cytoplasm of the cell
2) proportion of proteins will be Brocken into fragments by proteasome
3) fragments are transported into the ER by TAP transporter so protein is associated to MHC 1
3) MHC 1 becomes exported to the cell surface membrane

33
Q

Additionally when T cells engage with APC what stabilises the interaction

A

Molecular interactions (adhesion molecules)

34
Q

When would a T cell not be able to detect the tumour cell

A 
When there is a interference with:
MHC processing 
Molecular interactions (adhesion molecules) that stabilise the T cell interaction
35
Q

What are the mechanism when tumours can escape immune responce

A

Loss of MHC 1 expression
Reduced expression of molecules e.g TAP transporter involved in antigen presentation
Loss of co-stimulatory expression e.g CD80/CD86
Loss of adhesion molecules
Loss of target antigen
Inhibiting T cell infiltration
Immunosupression at tumour site

36
Q

What are the 2 ways of inhibiting T cell infiltration to tumour sites

A

1) endothelins b receptor on the tumour epithelium signals to prevent modulation of ICAM on vascular endotherlium to T cell cannot adhere to the vasculature
2) nitrosylation of chemokines that attract T cells so T cells aren’t attracted

37
Q

What are the ways of immunosuppression at the tumour site

A
  • Tumour cell expresses immunosuppressive cytokines
  • t reg cells
  • myeloid derived suppressor cells
38
Q

What is the role of t regulatory cells

A

Control normal T cells so they are not out of control

39
Q

What can high number of t reg do

A

Play a role in immune escape

40
Q

What are myeloid derived suppressor cells

A

A heterogenous cells of myeloid origin that have myeloid progenitor cells, immature macrophages, granulocytes and dendritic cells

41
Q

What happens to myeloid derives suppressor cells during cancer

A

Expand

42
Q

In cancer what does myeloid derived suppressor cells increase

A

Immune suppressive factors called arginase 1 and iNOS

43
Q

What does arginase 1 and iNOS metabolise

A

L-arginine

44
Q

What does loss of l-arginine inhibit

A

T cell proliferation

45
Q

What are the 3 T cell based therapies for cancer

A

Non specific T cell stimulation
Vaccination
Adaptive T cell therapy

46
Q

What does non-specific T cell stimulation involve

A

The use of immunostimulatory cytokines (toxic)

Blockage of immunologic checkpoints

47
Q

Describe the blockage of immunologic checkpoints

A

1) administer antagonist antibody
2) antagonist antibody binds to CTLA-4 (negaitve co-stimulatory molecule of T cell function)
3) blocking CTLA-4 means CD28 can bind to CD80/CD86

48
Q

Name an antagonistic antibody used in non specific T cell stimulation to target CTLA-4

A

Ipilimumab

49
Q

What cancer is ipilimumab used in

A

Melonoma

50
Q

Name another antagonist antibody that blocks PD1 binding to PDL1/2 on tumour cells for negaitve co-stimulation

A

Pembrolizumab

51
Q

What cancer is pembrolizumab used in

A

Melonoma

52
Q

In vaccination what do we give

A

Irradiated tumour cell
Protein antigens
Dendritic cell based vaccines

53
Q

What does adaptive T cell therapy involve

A

1) Injecting T cells from patient or a donor

2) T cell expands to give lots of T cells that target the tumour antigen

54
Q

In what cancer is adaptive T cell therapy used in

A

Melonoma

55
Q

How do we generate T cells rapidly

A

1) A T cell receptor gene is transferred to a T cell

2) T cell codes for the specific receptor and targets the cancer

56
Q

What are the potential side effects of T cell based therapy

A

Autoimmunity

Make tumour worse by enhancing angiogenesis

57
Q

What are the other treatments in cancer

A

Monoclonal antibodies

58
Q

What does antibodies recognise

A

Antigens on cell surface

59
Q

What are the mono-clonal antibodies immune mediated mechanism

A

1) antibody mediated lysis

2) Antibody dependent cellular cytotoxicity

60
Q

How does complement mediated lysis work in monoclonal antibody

A

1) The antibody binds to target antigen
2) Complement cascade is activated
3) MAC is produced
4) MAC punches a hole in the cell so lysis occurs

61
Q

What is antibody dependent cellular cytotoxicity (ADCC)

A

1) antibody bind to the antigens
2) NK cells recognise the antibody
3) NK cells kill the tumour cell

62
Q

What are the direct effects of monoclonal antibodies in cancer therapy

A

1) blocking receptor ligand interaction
2) prevent angiogenesis
3) cytotoxic activity of conjugated antibodies

63
Q

How does monoclonal antibodies prevent angiogenesis

A

Bind to agonist E.G Vegf

64
Q

What is cytotoxic activity of conjugated antibodies

A

Antibody delivers toxic molecule to the tumour such as radionuclide

CAN (25 decks)

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