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cancer > 23&24. tumour immunology > Flashcards

23&24. tumour immunology Flashcards

1
Q

what did it take 20 years of research to show?

A

that the immune system could be used to control tumour growth for immunotherapeutic cancer therapy

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2
Q

what are immune checkpoints? and how is this implicated in therapy?

A

these are inhibitory pathways hardwired into the immune system that are crucial for maintaining self tolerance
>tumours can utilise these pathways for immune resistance - particularly against T cells for tumour antigens
>we can blockade checkpoints in immunotherapy

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3
Q

how did the former US present benefit from immunotherapy?

A

he was cured of metastatic melanoma at the age of 90 (immune system is weak when old and he was still able to reject tumours)

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4
Q

what occurs every day in terms of surveillance?

A

tumour surveillance - it can illuminate cells that are not normal

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5
Q

what is the pre-neoplasm stage of cancer?

A

a single mutation in cells that can be revered by cell intrinsic repair methods

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6
Q

what is cancer? and how long can it take to develop?

A

progressive build-up of many different mutations over time, 5-20 years

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7
Q

describe why colon cancer has been useful in understanding cancer progression?

A

polyps are initially benign (non-neoplastic lesions), these can develop into cancer if not removed

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8
Q

why is kidney cancer hard to detect?

A

people only know there is a problem when they start seeing symptoms - blood in urine and urination problems - these are a consequence of the mass of the tumour and so kidney - by this time the cancer is at an advanced stage

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9
Q

paper defining the hallmarks of caner was published in 2001, and amended in 2011. what two things were added?

A

genomic instability and mutations

deregulation of cellular energetics

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10
Q

what might potentially be added to an undated of this review?

A

evade elimination by the immune system

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11
Q

what can cancer cells do in a tissue in terms of other non cancerous cells?

A

they can conscripted and subverted normal cell types to serve as active collaborators in their neoplastic agenda

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12
Q

what type of cells contribute to the environment and the progression of the tumour? comment on their abundance

A

stromal cells such as fibroblasts and epithelial cells

>their presence will vary from patient to patient and between different stages of progression

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13
Q

why was the fact that the immune system could detect and eliminate tumour cells controversial?

A

there was a lack of experimental evidence until about 10 years ago

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14
Q

why are solid tumours likely to develop later in life?

A

the immune system is weaker

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15
Q

some medication can make people more susceptible to certain types of cancer, what drugs are these? and why is this?

A

immunosuppressants
>latent pre-malignant tumours cells which were once under control of immune system will progress towards more clinically detectable tumours

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16
Q

in 1909 it was hypothesised that immune system might repress tumour growth. 50 years later, what was shown?

A

> the concept of immunological surveillance via recognition of tumour specific antigens, T cells can recognise these antigens

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17
Q

in the 70s what was shown about nude mice?

A

they were not more cancer prone, this shut down the idea of immunosurveillance

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18
Q

why are mice deficient in B and T cells not more cancer prone?

A

they have NK cells

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19
Q

what evidence for tumour surveillance is there? (4)

A
  • spontaneous regression of cancer is associated with injection and suggest that immune response may be responsible for tumour rejection
  • Immunocompromised individuals are more susceptible to certain types of cancer
  • presence of tumour infiltrating lymphocytes correlates with better prognosis
  • mice deficient in key components of immune system have increased incidence of tumour
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20
Q

what was suggested could predict human colorectal tumour outcome? what did this study do?

A

type, density and location of immune cells

  • characterised TILs in many patients colon cancer
  • correlated this with prognostic and grade
  • proved immunological data was better prediction of survival than current methods
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21
Q

what is an immunoscore?

A

the measure of TILs as a read out for the patients prognosis and a way to stage tumours - this provides accurate prognosis regardless of molecular read out

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22
Q

how can we KO key components of the immune system in mice to compare rate of tumourigenesis? and what sort of things can this affect? and what happens to these mice? and what does this show?

A 
CRISPR 
>B and T cells 
>interferon signalling 
>MHC class I expression 
>TRAIL expression
=they develop certain types of tumours 
different parts of immune system are more important in certain types of tumours
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23
Q

human tumours are immunogenic what does this mean?

A

there are tumour specific antigens which there are T cells specific to
>tumour cells can be recognized by the immune system

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24
Q

what was the first tumour antigen identified? and where is tis found?

A

MAGE (melanoma associated antigens)

>this is present in lots of types of cancer

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25
Q

name primary lymph nodes

A

bone marrow and thymus

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26
Q

name secondary lymph nodes

A

spleen, tonsils and lymph nodes

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27
Q

what happens if an infection occurs?

A

lymph node draining - the immune system will produce immune cells from the nearest lymph node

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28
Q

name 7 immune cells

A 
T cells 
Cytotoxic T cells (CD8) 
NK cells 
helper T cells (CD4) 
B cells 
plasma cells 
regulatory T cells
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29
Q

which cell types produce perforin enzymes which result in the destruction of their target

A

cytotoxic T cells and NK cells

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30
Q

where does specificity in the immune system come from?

A

B cells - interact with antigens and become activated, differentiate into plasma cells and produce antibodies

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31
Q

what happens when mice exposed to irradiated tumour cells are exposed to the cells again?

A

immune cell memory results in tumour cells being rejected when injected viable

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32
Q

what cells are important and present in the tumour environment?

A

T regs - these regulate the relative concentrations of Th1 and Th2 cells

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33
Q

what do Th1 cells produce and what does this do?

A

gamma interferon, IL-2, TNFbeta

this recruits macrophages

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34
Q

what do Th2 cells produce and what does this do?

A

IL-3 IL-4 IL-5 IL-10
>these are responsible for strong antibody production
>eosinophil activation
>inhibit macrophages i.e. phagocytosis-independent response

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35
Q

name 5 cells of the innate immune system

A

dendritic cells, macrophages, NK cells, NKT cells, lymphocytes

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36
Q

why are markers apparent on tumour cells?

A

induced upon cellular stress and DNA damage - innate immune system recognise molecules that are upregulated upon stress

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37
Q

name two tissue resident presenting cells

A

dendritic cells, macrophages, lymphocytes

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38
Q

what type of response does the innate immune system supply and what enhances this?

A

phagocytosis and ADCC - antigen dependent cell mediated cytotoxicity
>they are enhanced by adaptive immunity

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39
Q

what does the innate immune cells in tissue secrete?

A

cytokines and chemokines which promote inflammation and recruit macrophages

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40
Q

what do adaptive immune cells recognise and what are these cells?

A 
recognize tumour antigens
T cells (TCR/MHC recognition) 
B cells (produce specific antibodies)
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41
Q

when innate immunity changes the adaptive response what happens?

A

there is increased activity by NK cells
macrophages are engulfed by DC which migrate to draining lymph node to display antigens to niave T cells
>tumour specific T cells home to tumour along chemokine gradient

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42
Q

what are NK activated by?

A

cytokines released by macrophages and myeloid cells e.g. IL-1 and IL-12

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43
Q

what do NK cells recognised and what then happens?

A

ligand on target cells

>they form synapse between cells to deliver kill

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44
Q

what do NK cells secrete to kill cell?

A

perforin - make pores in membrane

granzyme - activates caspase pathway

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45
Q

what receptor is associated with disease state and what does it bind? and what does this lead to?

A

Fas receptor bind Fas ligand on cytotoxic T cells

>when receptor is activated this leads to apoptosis

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46
Q

where is the TRAIL receptor found?

A

on tumours cells

>binds cytokine TRAIL and results in apoptosis

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47
Q

what is found on the surface of all nucleated cells and what does it display

A

MHC1

>self antigens

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48
Q

what type of signal is MHC1 to NK cells?

A

an inhibitory signal - this is strong than positive signals on normal cells

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49
Q

what happens in autoimmune disease?

A

the inhibitory signal of MHC1 is dsyregulated and NK cells attack self cells

50
Q

what is the missing self hypothesis

A

cancer cells down regulate MHC1 to try and evade T cell mediated immune responses
>removing this is not enough to activate NK cells - they need a positive signal as well

51
Q

what two ways can NK cells be activated?

A
  1. removal of MHC1 allows positive signal to take over

2. target cell maintains MHC1 but upregulates activating signal due to cellular stress, this overpowers inhibition

52
Q

how does the NK cells decide if the tissue is in danger?

A

the balance between positive and negative signals

53
Q

NK cells can also deliver kill by antibody dependent cell mediated cytotoxicity, describe this

A

> antibody production is the result of B cells activation in response to antigen
antibody binds antigen on tumour
NK cells bind Fc portion via Fc receptor
this activates NK cells - use cytotoxicity to lyse cells through degranulation

54
Q

what receptor is found on NK cells and CD8+ cells?

A

NKG2D

55
Q

what do CD8+ cells recognise MHC1 through?

A

TCR

56
Q

when NKG2D interacts with ligand on target cells what happens

A

> this activates NK cells (stimulatory)

>in the case of CD8+ T cells these also need to bind MHC1 (co-stimulatory)

57
Q

what happens when cells are activated through NKG2D?

A

they have cytotoxic activity (perforins and granules) which kills target cells

58
Q

shortly describe the DNA damage pathway

A

DNA damage recognised by ATM and ATR, these P chk2 and p52, Chk2 P p53 –> cell cycle arrest/apoptosis

59
Q

what does the DNA damage pathway induce?

A

> Chk1 and Chk2 lead to NKG2D

ligand upregulation

60
Q

what do normal healthy cells rarely express? and why is this?

A

NKG2D ligand

the ligand flags a cell as stressed

61
Q

what are cells expression NKG2D?

A

these are cells that are not tumour cells although these cell could potentially become tumorigenic is not destroyed

62
Q

describe the structure of NKG2D

A

dimeric transmembrane protein

63
Q

in humans, what is associated with NKG2D?

A

DAP10 - adaptor proteins which helps mediate signal transduction

64
Q

what cells is NKG2T expressed on?

A
  • NK cells
  • NKT cells
  • γδT cells
  • activated CD8+ cells
  • CD4+ cells under certain circumstances
65
Q

how many ligand are there for NKG2T? what are they like and what regulated them?

A

there are several
>all have MHC1 related domains
>upregulated in response to cellular stress
>expression of ligand is regulated at either transcriptional or post-transcriptional level

66
Q

some NKG2D ligands can be cleaved from cells surface, what are soluble ligands a marker of? and why is this?

A

advanced cancer

>tumours cells lose them from their surface (like they lose MHC1) to escape immune surveillance

67
Q

what happens when NKG2D ligand is ectopically expressed on tumour cells? and what does this prove?

A

this results in tumour cell rejection

>this proves the importance of NKG2D pathway

68
Q

what happens in KO NG2TD mice?

A

they are more tumour prone

69
Q

give an example of an NKG2D in mice

A

Rae1

70
Q

what happens when anti-NKG2D is injected along with tumour cells into mice?

A

rapid growth of tumour, similar to that in mice that don’t have NKG2D

71
Q

what happens is the mutated cell escapes immune surveillance? give an example

A

this will lead to the formation of cancer

>if both p53 are mutated, a p53 response will not be triggered and so cells will no express NKG2D ligand

72
Q

how are effector T cells made? what do they do?

A

> TRC binds MHC1
CD28 binds B7.1
co-stimulatory signals
these cells become effector T cells - these can activate memory cells (T and B cells that have seen an antigen before)

73
Q

what type of tumour antigen can adaptive immunity recognize?

A
  • tumour specific antigen
  • tumour associated antigen
  • viral antigen
74
Q

describe tumour specific antigens

give an example

A

> generated by spontaneous mutation
not expressed on normal cells
very rare
they can be unique or shared (e.g. MAGE)

75
Q

describe tumour associated antigens

give an examples

A

> over expressed self antigens e.g. Her2/neu - cells expressing Her will be targeted by immune system
and PSA
differentiation antigens - these are self proteins expressed at wrong stage of development e.g. carcinoembryonic antigen in colon cancer

76
Q

how are cells expressing Her2 not being therapeutically targeted

A

antibodies that recognise Her2 and so disrupt its interaction with GF

77
Q

describe viral antigens

give example

A

non self proteins

expressed by viral genome

78
Q

name 2 types of viruses that can integrate into host genome

A

retrovirus (RNA)

provirus (DNA)

79
Q

give example of DNA tumour viruses (3) and what can they induce?

A

HPV, SV40 and RSV

these can induce different types of cancer

80
Q

what are the three Es of cancer?

A

elimination
equilibrium
escape
they describe how tumour avoid immunosurveillance

81
Q

what is cancer immunoediting?

A

when cancer cells down regulate molecules on their cell surface in order to escape the immune system

82
Q

what does elimination correspond to?

A

immunosurveillance - both adaptive and innate immune system eliminated clones displaying tumour specific antigens

83
Q

describe the tumour at the elimination stage

A

it is clinically invisible

84
Q

how will the individual be if eq is maintained?

A

they will remain healthy

85
Q

what might shift the equilibrium and allow for tumour progression?

A

immunosuppression

86
Q

what are selected for during the equilibrium phase?

A

tumour variants with increasing capabilities to survive the immune attack

87
Q

what may happen at the end of the eq phase?

A

mutations may arise where cells out compete the immune system due to constant immune pressure - they might loss antigen presenting and/or induce immunosuppression

88
Q

what happens in the escape phase?

A

rapid proliferation of resistant clones in the immunocompetent host
>by this stage the tumour is clinically detectable

89
Q

in addition to stress induced molecules, MHC1 and NKG2D, what else is expressed on tumour cells in elimination phase and what are they?

A

Fas and TRAIL receptor

these are apoptotic receptors

90
Q

describe what happens in terms of CD8+ cells and NK cells in the elimination phase

A

> tumour expresses MHC1, NKG2D, Fas and TRAIL receptor
this activated CD8+ and NK cells
cytotoxic effector cells such as NK, CD8+ and NKT (activated by DC), induce apoptosis by interacting with Fas/TRAIL receptor - release perforin, granzymes, INFγ in the tumour microenvironment

91
Q

what do DC do in the elimination phase?

A

> DC take up and cross present antigens to T cells and NKT cells
effector T cells express co-stimulatory molecules to enhance their proliferation and survival - release perforin, granzymes, INFγ in the tumour microenvironment

92
Q

what addition cells plays a role in elimination phase and what does they do?

A

macrophages and granulocytes contribute to anti-tumour environment - excrete TNFα, IL-1, IL-12 and ROS

93
Q

what is the balance between in the eq phase?

A

anti-tumour/inflammatory cytokines (IL-2, IFNγ) and tumour promoting/immunosuppressive cytokines (IL-10, IL-23)

94
Q

what is required to maintain tumour in a dormant state ?

A

adaptive immune system

NK cells are dispensable

95
Q

what can break the balance in the eq phase?

A

IL-17

96
Q

how can you determine which cytokines/interleukins are involved in the equilibrium phase?

A

> inject mice with carcinogen
mutations slowly arise
inject antibodies against certain cytokines/interleukins combinations to try and figure out which of these are involved in the equilibrium while mice are tumour free
important ones allow expansion of tumour - anti-CD4, anti-CD8, anti-INFγ

97
Q

why does anti-CD4, anti-CD8, anti-INFγ impair equilibrium phase?

A

> anti- INFγ binds INFγ and prevents it from biding CD8 cells
anti-CD8 blocks CD8 and depletes these cells – macrophages eliminate these CD8 cells due to the antibody bound to them (ADCC -antibody dependent cell mediated cytotoxicity)

98
Q

name four ways that tumour cells can escape the immune system

A

> escape the recognition by tumour editing - loss or gain of molecules to escape recognition
escape elimination - mutations make them more resistant to apoptosis
coerce the inflammatory milieu
counterattack

99
Q

what might a tumour lose in order to escape attack? (4)

A

loss of NKGTD
loss of tumour antigen
induction of inhibitory ligand expression e.g. for NK cells
deregulation of MHC1 molecules

100
Q

describe CD8+ cells and how they are activated

A

CD8+ cytotoxic T cells have TCR and CD28 on naïve cells. they are activated by APCs to become effector cells. they upregulate CTLA4 and PDL. if tumour has PD and B7.1 CD8+ cell will bind.

101
Q

what will block CD8+ cells?

A

upregulation of inhibitory ligands on tumour cells will block the efficiency of CD8 cells.

102
Q

tumour acquire additional mutations to escape elimination, give an example of this?

A

resistance to apoptosis increase anti-apoptotic Bcl-1

103
Q

how can tumour cells coerce the inflammatory milieu?

A
  • release immunosuppressive and pro-antigenic factors
  • promotes activity of T reg cells and immunosuppressive cells
  • T regs released immunosuppressive cytokines
104
Q

how do tumours recruit T reg cells?

A

through chemokines

105
Q

what happens to T cells once the injection/tumour is gone and why does this happen?

A

they undergo passive death as they are no longer getting survival signals

106
Q

how is Fas used in passive death of T cells?

A

Fas and Fas ligand are both expressed on T cells when you have persistent antigen stimulation
>Fas binding to Fas ligand results in apoptosis in T cells

107
Q

why do we want passive death of T cells?

A

don’t want them continuously active creating inflammation

108
Q

what does long term inflammation leads to?

A

dysplasia – the enlargement of an organ or tissue by the proliferation of cells - this is the early stage of cancer development

109
Q

how do tumour cells counterattack CD8+ cells?

A

they upregulate the expression of Fas ligand

>this binds Fas on CD8+ cells and induces apoptosis

110
Q

name thee cells types that impair tumour surveillance? and what do they cells do? and what attracts them to the tumour?

A

T reg cells
myeloid derived suppressive cells (MDSC)
tumour associated macrophages (TAM)
>they impair the immune response and help the tumour grow
>chemokines and cytokines

111
Q

what do T reg do

A

> inhibit effect T cells by releasing immunosuppressive cytokines
release granzyme A/B and perforins which causes cytolysis of effector T cells
cytokine deprivation induce apoptosis of cytoxic T cells (IL-2 binds CD25 on T reg)
they target mechanisms that regulate DC maturation and function
upregulate PD-L1 which inhibit PD expressed on memory T cells

112
Q

what are myeloid derived suppressive cells derived from? and what are they?

A

immature myeloid cells

>heterogeneous population of early myeloid cells, immature granulocytes, macrophages and DC

113
Q

what do myeloid derived suppressive cells do?

A

supress the cytoxic activity of NK and NKT cells

>mediate response of CD4+ and CD8+ cells

114
Q

what induced myeloid derived suppressive cells and where are they found?

A

pro-inflammatory cytokines
they are found in infections and inflammation
>they accumulate in the blood, BM and 2ndary lymph of tumourgenic mice

115
Q

MDSC are a key therapeutic target although they are not properly characterised, why is this? and what distinguishes them?

A

they are hard to study as it is hard to distinguish them from other myeloid cells
>they have a slightly more immature phenotype
>they are granular
>present at site of injury and circulation
>not present in healthy individuals

116
Q

what can MDSC differentiate into? how are they distinguished from MDSC?

A

TAM (tumour associated macrophages)

>functional assay

117
Q

how MDSC mediate their suppressive function in secondary lymph nodes? and what does this specifically supress?

A

> present antigens to CD8+ cells
produce ROS
nitration and nitrosolyation of aa on TCR and CD28
TCR less stable
T cells unresponsive to antigen specific stimulation
-this specifically supresses T cells that are specific to antigen in tumour environment and so only inactivates clones which are able to target the tumour

118
Q

how do MDSC mediate their suppressive function in the tumour environment?

A

> produce high levels of iNOS, NO and arginase 1
arginase 1 catalyses the reaction of argine and water to ornithine and urea - shortage of arginine inhibits T cells proliferation through several different mechanisms (prevent upregulation of some cyclin/cdk)
NO supresses T cells function by inhibiting JAK STAT

119
Q

what do TAM secrete?

A

they also secrete immunosuppressive cytokines:
>these inhibit T cells ability to proliferate and reduce their capacity to interact with tumour cells
>promotes t cells apoptosis
>also have -ve effect on T cells activation

120
Q

what are the main two cells types that cooperate to reject tumours cells?

A

NK cells and cytotoxic T cells

121
Q

what do cytotoxic T cells recognise?

A

tumour specific antigens, tumour associated antigens and viral antigens

122
Q

how can cancer cells escape immunosurveillance?

A

being less recognize (immunoediting) and/or generating a immunosuppressive environment

cancer (24 decks)

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