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AI - Cancer Immunology > Tumour Immunology > Flashcards

Tumour Immunology Flashcards

1
Q

What is the evidence for spontaneous tumour regression? And what causes the regression?

A

Viral infection boosted the immune response in cancer patients and caused regression of the tumour - even though the infection did not trigger a tumour-specific response. Suggested that the immune response may be responsible for tumour rejection.

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2
Q

What are the 5 initial pieces of evidence for tumour surveillance by the immune system?

A

1) Spontaneous regression
2) Spontaneous tumour formation in immunocompromised individuals.
3) Improved prognosis associated with tumour infiltrating lymphocytes, detected through immunohistochemistry.
4) Nude mice are more cancer prone.
5) Tumours expressing TSA are attacked by immune cells - MAGE epitopes discovered in melanoma.

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3
Q

How can tumour cells activate NK cells?

A

Through downregulation of MHC class I - allowing activatory signals to become dominant. Through expression of NKG2D ligands.

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4
Q

Give examples of the innate immune cells involved in tumour surveillance.

A

Gamma-delta T cells, NK cells, NKT cells, macrophages and dendritic cells

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5
Q

Why are HIV sufferers more cancer prone?

A

They are immunocompromised, and there is less immune surveillance of tumours.

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6
Q

Name the types of antigens expressed by tumour cells.

A

Tumour specific (TSA), Tumour associated (TAA) and viral antigens.

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7
Q

What are viral antigens?

A

Non-self proteins that are encoded in the viral genome and are expressed by infected cells.

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8
Q

Give the cytokines released by macrophages upon recognition of tumour cells.

A

IFNy and IL-12 - these are anti-tumour cytokines.

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9
Q

Describe the equilibrium phase.

A

Selection of resistant tumour cells. Equilibrium is maintained by the immune system, through secretion of anti-tumour cytokines.

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10
Q

What does IFNy stimulate?

A

Activation of T cells, and further production of IFNy.

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11
Q

Give the cytokines that activate NK cells.

A

IL-2, IL-12, IL-15, IL-21 and IFNa.

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12
Q

How do NK cells kill tumour cells?

A

Triggering of apoptosis in the tumour cell, via the release of perforin, and other cytotoxic granule proteins.

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13
Q

Give the 3 E’s of cancer immunoediting.

A

Elimination, Equilibrium and Escape.

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14
Q

Give examples of tumour promoting cytokines.

A

IL-10 and IL-23 (IL-23 activates MMP9, promotes angiogenesis and limits CD8+ T cell infiltration into tumour).

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15
Q

What is ADCC?

A

Antigen Dependent Cell-mediated Cytotoxicity

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16
Q

Give the NK cell receptor involved in ADCC.

A

CD16 - recognises the Fc portion of antibodies.

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17
Q

What is the function of NKG2D?

A

Activatory receptor on NK cells, that binds the MICA/MICB stress ligands and ULBPs.

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18
Q

What causes expression of NKG2D ligands?

A

The DDR - damage recognised by ATM/ATR, which phosphorylates p53 and Chk1/2 which further phosphorylates p53, resulting in transcriptional upregulation of stress ligands.

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19
Q

What causes the generation of TSAs?

A

Spontaneous mutations in tumour cells.

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20
Q

What is a shared antigen?

A

A TSA that is expressed by many independent tumours.

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21
Q

What is a unique antigen?

A

A TSA that is expressed by one tumour, or very few tumours.

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22
Q

Why are there different time frames for tumour progression in different tissues?

A

Different mutations are more likely to occur in different tissues, and different tissues have various levels of blood supply access.

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23
Q

When does cancer occur?

A

When normal tissue state cannot be recovered and there has been gain of mutations that allow for metastasis.

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24
Q

What does tumour progression depend on?

A

Quality of the immune response

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25
Q

What is immunoscore?

A

A diagnostic method that uses a grading system of the immune cell presence to predict prognosis - described in colorectal cancer.

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26
Q

Give examples of genes that were demonstrated as important in tumour surveillance.

A

Rag2, IFNy, STAT1 (response to IFNy signalling), TRAIL and NKG2D

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27
Q

How are tumours initially recognised by the immune system?

A

NK, NKT and gamma/delta T cells patrol in tissues and detect tumours. Release of IFNy upon activation on these cells, recruits CD8+ T cells to the tumour site.

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28
Q

Describe the role of DCs in the very early stages of tumorigenesis.

A

DCs collect antigen released by dying tumour cells, and present this to B/T cells in the lymph nodes - activating the adaptive immune responses.

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29
Q

Give the cytokines released by activated NK cells.

A

IFNy and TNFa

30
Q

Give cells that express the NKG2D receptor.

A

NK, NKT and gamma/delta T, CD8+ T cells - and in some cases CD4+ T cells

31
Q

When are T cells better activated by NKG2D?

A

If they have already encountered the antigen, and the TCR has been stimulated.

32
Q

Why is it unlikely that a cancerous cell could bypass NKG2D recognition and NK cell attack?

A

NKG2D receptor responds to multiple ligands - it is unlikely that a cancerous cell could bypass all of these.

33
Q

Give evidence for the importance of NKG2D in tumour rejection. What are the limitations of this experiment?

A

Injection of tumour cells expressing RAE-1 into mice does not result in tumour growth. Injection of an antibody against RAE-1 causes tumour growth - no NK cell response.
Limitations - used a tumour cell line containing only a few cell types, a tumour would actually be much more heterogeneous. Tumour cells were induced to express RAE-1 to high levels (increased NK activity), in reality tumour cells may be expressing NKG2D ligands at much lower levels.

34
Q

When does immunosurveillance by NKG2D occur?

A

At the pre-cancerous stage, as this is when the DDR would be activated and would stimulate NKG2D ligand expression in the tumour cells.

35
Q

What does the efficiency of TCR/TSA interactions depend on?

A

What is expressed by the tumour cell - how much antigen is expressed and whether the costimulatory molecules are expressed (B7)

36
Q

What is the third signal required for full activation of T cells?

A

Presence of cytokines, e.g. IFNy.

37
Q

Give evidence for the importance of memory T cells in tumour rejection.

A

Mice injected with irradiated tumour cells become immunised against injection of viable cels from the same tumour.

38
Q

Give the 3 types of TAAs.

A

Overexpressed antigen, differentiation antigen and viral antigens.

39
Q

What is a differentiation antigen?

A

A self-protein that is normally expressed during foetal development and is normally absent in adult cells - expression can be switched on in tumour cells.

40
Q

Describe elimination.

A

Process of immunosurveillance. Effective at rejection if tumour cells express TSA and if occurring early on in the cancerous transformation and growth process. Relies on efficient presentation of TSA by DCs.

41
Q

How do macrophages (M1) and granulocytes contribute to anti-tumour immunity?

A

Secretion of TNFa, IL-1, IL-12 and ROS.

42
Q

Describe equilibrium.

A

The process by which the immune system promotes the generation of tumour cell variants, with increasing capacities to survive immune attack.

43
Q

What is held in equilibrium during the equilibrium phase?

A

Balance between anti-tumour and tumour promoting cytokines.

44
Q

How do resistant tumour cells evolve?

A

Tumour cells undergo genetic and epigenetic changes due to constant immune pressure, and variants evolve that are resistant to immune recognition.

45
Q

Describe escape.

A

The process by which the tumour cells can evade the immune system, and expand in an uncontrolled manner.

46
Q

How can tumour cells evade the immune system?

A
  • Loss of tumour antigen expression.
  • Loss of expression of activating NKG2D ligands.
  • Downregulation of MHC class I.
  • Expression of inhibitory ligands, e.g. PDL-1. /
  • Mutations that allow escape of elimination, e.g. overexpression of anti-apoptotic proteins.
47
Q

What is the result of downregulation of MHC class I expression in tumour cells?

A

Makes tumour cells less recognisable to T cells, but NK cells can recognise a loss of MHC class I expression.

48
Q

Give examples of immunosuppressive cytokines released by tumour and myeloid cells.

A

TGFb, IL-10

IL-6 and VEGF - pro-angiogenic

49
Q

What is the result of the release of immunosuppressive cytokines?

A

Promotion of Treg, MDSC, and TAM activity

50
Q

What are MDSCs?

A

Immature myeloid cells with immunosuppressive function. Only found during infection or at tumour sites. Induced by pro-inflammatory cytokines.

51
Q

What are TAMs?

A

TAM=Tumour Associated Macrophage

Negative macrophages that block the immune response, also derived from immature myeloid cells.

52
Q

Give an example of how tumour cells escape immune killing.

A

Upregulation of FasL - triggering apoptosis in FADD expressing immune cells.

53
Q

What does the immunosuppressive microenvironment promote?

A

Angiogenesis, allowing metastasis and escape from the primary site of tumour formation.

54
Q

How do Tregs contribute to the immunosuppressive microenvironment?

A
  • Act as an IL-2 sink, preventing T cell proliferation
  • Can release Granzymes A and B to induce apoptosis of effector T cells.
  • Recognition of Ag presented by DCs causes release of IDO from DCs.
55
Q

What is IDO and what does its release cause?

A

IDO = Indoleamine-2,3-dioxygenase

IDO kills T cells and inhibits dendritic cell maturation.

56
Q

What cells release IDO?

A

Dendritic cells - immature DCs in particular, and tumour cells.

57
Q

How does IDO limit T cell proliferation?

A

IDO catabolises tryptophan.

58
Q

How do MDSCs block the immune response?

A
  • Defective antigen presentation

- Secrete NO and arginase, affecting T cell proliferation.

59
Q

What is the ultimate point that makes a tumour almost untouchable?

A

Loss of p53 heterozygousity

60
Q

What is immunoediting?

A

Changes to the expression profiles of tumour cells to allow immune evasion.

61
Q

Give evidence of increased Tregs and exhausted T cells in the tumour bed.

A

Shown in hepatocellular carcinoma, using single cell RNA Seq and CyTOF. Exhausted T cells identified by PD1 and LAYN expression.

62
Q

What is the advantage of CyTOF?

A

Allows identification of up to 30 cell surface markers at one time. Allows identification of exhausted T cells - not detected by immunoscore.

63
Q

Why is it important to map the tumour bed?

A

Allows better predication of whether the immune response will be able to reject the tumour and identifies which immunotherapeutic approaches could be used.

64
Q

Why do MDSCs have impaired antigen presentation?

A

ROS and arginase activity decrease expression of CD3 costimulatory molecule, and TCRs cannot be efficiently activated.

65
Q

What is the result of peroxynitrite production by MDSCs?

A

Nitration and nitrosylation of amino acids in TCR and CD8 molecules - makes the T cell unresponsive to antigen-specific stimulation.

66
Q

How does arginase contribute to immune suppression?

A

Depletes L-arg, inhibiting T cell proliferation and expression of CD3 zeta chain.

67
Q

How does NO suppress T cell function?

A
  • inhibition of JAK3/STAT5
  • inhibition of MHC class II expression
  • induction of T cell apoptosis
68
Q

What enzyme is responsible for NO production in MDSCs?

A

Inducible NOS (iNOS)

69
Q

Give the consequences of immunosuppressive cytokines released by TAMs.

A

IL-10 and TGFb - inhibit CD8+ T cell proliferation, induce apoptosis and induce Treg production.

70
Q

What is the consequence of M2 macrophages in the tumour bed?

A

Promote tumorigenesis and contribute to angiogenesis.

71
Q

Give examples of cytokines associated with a worse prognosis when present in the tumour bed.

A

Th2 cytokines (IL-4, IL-12, IL-13) and Th17 release of IL-17 (causes overinflammation).

72
Q

How can Th17 cells have some anti-tumour activity?

A

Via the recruitment of NK cells and CD8+ T cells.

AI - Cancer Immunology (3 decks)

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