Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Year 2 - MCD - Immunology > 1 - Tumour Immunology and Immunotherapy of Cancer > Flashcards

1 - Tumour Immunology and Immunotherapy of Cancer Flashcards

1
Q

How does a positive antibody test stain?

A

brown (-> shows Ig binding)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

CDR2

A

CDR2 = cerebellum degeneration-related antigen 2

  • can be made in breast cancer
  • paraneoplastic
  • patient made ABs against the tumour, these ABs went to her brain and caused these symptoms
  • Spontaneous immune response against tumour-expressed antigen results in auto-immune disease
  • Purkinje cells that express this AG are not there anymore, they were destroyed causing neurological disease
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Purkinje cells

A

type of motor neurone in the cerebellum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is a problem in the immunology of cancer?

A
  1. At least certain tumours can express antigens that are absent from (or not detectable in) corresponding normal tissues.
  2. The immune system can, in principle, detect such abnormally expressed antigens and, as a result, launch an attack against the tumour.
  3. In certain cases, this may result in auto-immune destruction of normal somatic tissues.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is some evidence for immune control of tumours in humans?

A
  1. Autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease. Immune control?
  2. Patients treated for melanoma, after many years apparently free of disease, have been used as donors of organs for transplantation. Transplant recipients have developed tumours. Donor had developed ‘immunity’ to the melanoma, but the transplant recipients had no such ‘immunity’.
  3. Deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy
  4. Men have twice as great chance of dying from malignant cancer as do women (women typically mount stronger immune responses)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Tumour immunosurveillance

A

Concept of tumour ‘immunosurveillance’: malignant cells are generally controlled by the action of the immune system.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the goal of immunotherapy?

A

Immunotherapy tries to enhance immune responses to cancer.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

T-cells vs B-cells

A

T-cells

  • alpha-beta T receptor
  • MHC restricted (class 1 and class 2)
  • helper t-cells, cytotoxic t-cells

B-cells

  • B-cell receptor (=membrane bound antibody)
  • vast range of molecules
  • e.g. virus neutralisation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Cancer Immunity Cycle

A
  1. when a cancer cell dies there is release of cancer cell antigens
  2. These cancer AGs are presented in dendritic cells and other APCs
  3. Priming and activation to APCs and T-cells
  4. trafficking of T-cells to tumours (CTLs)
  5. Infiltration of T-cells into tumours (CTLs, endothelial cells)
  6. Recognition in cancer cells by T-cells (CTLs, cancer cells)
  7. Killing of cancer cells (immune+cancer cells) -> cycle repeats

BUT: this cycle is related to selective pressure, certain cells will be selected against whilst others might be selected for. Variance.
-> this is a problem with immunotherapy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

TIL

A

= tumour infiltrating lymphocyte

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Immune checkpoint blockade

A

There are factors in the cancer immunity cycle that up- and down regulate T-lymphocyte stimulation.

  • immune checkpoint blockade can be used to inhibit the inhibitory factors and therefore increase the number of t-cells and strengthen a potential respose against the cancer cell
  • gives rise to selective pressure.
  • Examples:
    • PD-L1/B7
    • PD-L1/PD.1
    • CTLA4/B7.1
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What initiates cancer usually?

A
  • Initiation of cancer usually results frommultiple sporadic events over time
  • irradiation
  • chemical mutagens
  • spontaneous errors during DNA replication
  • tumour-virus induced changes in genome.
    => induction of mutation in cellular DNA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What results in tumour growth?

A
  • Aberrant regulation of apoptosis and cell cycleresults in tumour growth
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Recruitment of immune cells to tumours

A
  • Tumour growth (eventually) results ininflammatory signals (it has to reach a certain size)
  • this recruits the innate immunity and gets immune cells there (dendritic cells, Macrophages, NK-cells)
  • go to draining lymph node
  • and subsequent recruitment of adaptive, antigen-specific immunity (B cells and T cells)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the requirements for activation of an adaptive anti-tumour immune response?

A
  1. Local inflammation in the tumour (“danger signal”)

2. Expression and recognition of tumour antigens

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the problems in immune surveillance of cancer?

A
  1. It takes the tumour a while to cause local inflammation
  2. Antigenic differences between normal and tumour cells can be very subtle (e.g. small number of point mutations)-> you have to be able to distinguish between these small differences
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Cancer Immunotherapy

A

If requirements for ‘spontaneous’ activation of the adaptive anti-tumour response are not met, can we ‘teach’ the adaptive immune system to selectively detect and destroy tumour cells? -> IMMUNOTHERAPY

  • Potential alternative/supplement to conventional therapies (surgery, chemotherapy, radiotherapy) -> very useful in conjunction with other therapies.
  • Which antigens should be targeted?
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How is the immune response to viruses and cancer cells similar?

A
  • T cells can ‘see’ inside cells, and canrecognise tumour-specific antigens
  • they see surface fragments that are representative of tumour specific antigens.
  • ‘Display’ contents of cell for surveillance by T cells: infection, carcinogenesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Tumour-specific antigens

A
  • viral proteins (EBV, HPV)
  • mutated cellular proteins (TGF-beta receptor 3; fusion proteins e.g. bcr-abl, fusion creates new sequence which is not found in genes)
  • tumour specific antigens are only found in the tumour,.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is the difference between tumour specific and tumour associated antigens?

A

TSA: only found in tumours

TAA: Tumour-associated antigens (TAA) are normal cellular proteins which are aberrantly expressed (timing, location or quantity).

21
Q

Cancers of viral origin

A

Opportunistic malignancies: Immunosuppression
• EBV-positive lymphoma: Post-transplant immunosuppression
• HHV8-positive Kaposi sarcoma: HIV

Also in immunocompetent individuals:
• HTLV1-associated leukaemia/lymphoma
• HepB virus- and HepC virus-associated hepatocellular carcinoma
• Human papilloma virus-positive genital tumours

22
Q

Cervical cancer

A
  • may be due to HPV infection
  • decreased after the introduction of the HPV vaccine
  • cervical cancer is induced and maintained by E6 and E7 oncoprotein in HPV - intracellular antigens
23
Q

Target antigens for preventive HPV vaccination

A
  • Surface proteins, incorporated into Virus-Like Particles (VLPs)
  • gardasil has 9 different subunits of HPV
  • also used in men for anal and genital wart prevention and also prevention of spread of the virus to partners?
  • E1,2,4,5 = early proteins
  • E6,7 = oncoproteins
  • L1, L2 = late proteins

The vaccine is just proteins! Not the virus.

24
Q

Relation between consequences of cervical HPVinfection and HPV-specific T cell immunity

A
  • 99% of people are able to fight and control the infection and don’t get cervical cancer even if they have HPV -> clearance of HPV and immunological memory
  • in a minority, there is immune failure -> cervical neoplasia, 50% no immunity, 50% non-functional immunity
  • if they do get cancer sometimes a therapeutic vaccine can still be used.

Preventative vaccination given to many people.

25
Q

Tumour associated antigens

A
  • Tumour-associated antigens (TAA) are normal cellular proteins which are aberrantly expressed (timing, location or quantity).
  • Because they are normal self proteins, for an immune response to occur tolerance may need to be overcome.
  • ectopically expressed auto-antigens
26
Q

Examples of tumour associated antigens

A
  • Cancer-testes antigens (developmental antigens): Silent in normal adult tissues except male germ cells (some expressed in placenta).
  • e.g. MAGE family: Melanoma associated antigens. Identified in melanoma also expressed in other tumours. (e.g. MAGE 3)
  • Human epidermal growth factor receptor 2 (HER2): overexpressed in some breast carcinomas
  • Mucin 1 (MUC-1): membrane-associated glycoprotein, overexpressed in very many cancers
  • Carcinoembryonic antigen (CEA): normally only expressed in foetus/embryo, but overexpressed in a wide range of carcinomas

PROSTATE

  • prostate-specific antigen (PSA)
  • prostate-specific membrane antigen (PSMA)
  • prostatic acid phosphatase (PAP)
27
Q

Tolerance induction in the thymus

A
  • central tolerance
  • Selection of T-cells in the thymus
  • positive (reacts to antigens) and negative selection (doesn’t react to own antigens)
  • to get rid of auto reactive cells but ensure that they are MHC restricted.
  • We all have self- reactive cells but this is normally not a problem
  • auto reactive T-cells are cells that have escaped selection in the thymus.
28
Q

What is the problem with targeting TAAs?

A
  • if you activate t-cells against TAAs, you might generate an AI response against healthy tissue
  • e.g. Immunotherapy against melanoma in mice is accompanied by auto-immune skin depigmentation (vitiligo)
  • Local auto-immune depigmentation in melanoma patients (depigmentation around the lesion, body itself does this)
29
Q

What are the 2 major problems with targeting of tumour-associated auto-antigensfor T cell-mediated immunotherapy of cancer?

A
  1. Auto-immune responses against normal tissues
  2. Immunological tolerance
    • Normal tolerance to auto-antigens (not having the repertoire available to stimulate in the first place)
    • Tumour-induced tolerance (tumours induce tolerance, may release factors and may down regulate the immune response as well)
30
Q

Summarise approaches being used and developed for tumour immunotherapy

A

1) Antibody-based therapy
2) Therapeutic vaccination
3) Immune checkpoint blockade
4) Adoptive transfer of immune cells
5) Combinations of 1) to 4) above

31
Q

Monoclonal antibody-based therapy

A

“Naked”
- e.g. Trastuzumab (Herceptin®) anti HER2, anti CD20, anti CD52, anti EGFR

“Conjugated”

  • radioactive particle e.g. Ibritumomab tioxetan (Zevalin®), anti CD20 linked to yttrium-90
  • drug e.g. Trastuzumab emtansine (Kadcyla®), anti HER2 linked to cytotoxic drug -> deliver the drug to the tumour

“Bi-specific” antibodies
- Genetically engineered to combine 2 specificities, e.g. anti CD3 and anti CD19 (Blinatumomab, approved for use in patients with B cell tumours)

32
Q

-umab

A

human AB

33
Q

Therapeutic cancer vaccination

A
  • There is one FDA approved vaccine to treat cancer (also licensed for sale in the UK, but not NICE approved):
  • Provenge® (sipuleucel-T) for advanced prostate cancer
  • Patient’s own WBC are treated with a fusion protein between prostatic acid phosphatase (PAP) and the cytokine GM-CSF
  • Stimulates DC maturation and enhances PAP-specific T cell responses

REWACTH THIS PART

34
Q

“Personalised” tumour-specific cancer vaccines

A
  • WES (whole exam sequencing) of cancer cells and healthy cells
  • look at the differences
  • computer programmes are used to estimate which peptides will bind to HLA
  • use this info and add adjuvant (which helps stimulate the immune response)
  • VERY EXPENSIVE!! therefore not expected to be routinely used in foreseeable future.
35
Q

Immune checkpoint blockade (as immunotherapy)

A
  • mABs block interaction
  • advantage: this is a generally applicable approach, not tumour specific.
  • Rather than directly stimulate responses, this approach seeks to reduce/remove negative regulatory controls of existing T cell responses
  • Targets CTLA-4 and PD-1 pathways:
    - CTLA-4 is expressed on activated and regulatory T cells, binds to CD80/86 (costimulatory molecules on APC)
    - PD-1 is expressed on activated T cells, binds to PD-L1/L2 (complex expression patterns, may be upregulated on tumours)
    - e.g. Ipilimumab (anti CTLA-4), Nivolumab (anti PD-1), antagonistic antibodies

widely used in melanoma, but also used in other types of cancer.

36
Q

Adoptive cell transfer (ACT)

A
  • > expensive!!
  • boost number of tumour specific cells.
  • has to be controlled well

T-cell source -> (non specific TIL expansion, antigen specific expansion, genetic engineering) culture -> expansion -> re-infusion

  • you have the opportunity to genetically engineer the cells, you can change their specificity.
37
Q

TIL

A

tumour infiltrating lymphocyte

38
Q

CARs

A

= Chimaeric Antigen Receptors

  • CAR -T-cells
  • attacks cancer cells
  • very expensive
  • generally applicable but need to know the recoptor - just change the specificity of the CAR
39
Q

Summary

A
  • Some tumours express self proteins that are not found in the equivalent normal cells, and immune responses can be generated against these tumour-associated antigens.
  • There are also some tumour-specific antigens, for example in tumours caused by oncogenic viruses, and these may be recognised by the immune system.
  • Immune responses against tumours have some similarities with those against virus infected cells, in terms of mechanisms. However, tumours are much less inflammatory than infections, and therefore it is harder to generate lymphocyte responses against tumours than infections.
  • Two major problems in developing immunotherapy for tumours are autoimmune reactions against normal self tissue, and breaking immunological tolerance against self. These problems don’t apply for viral tumour antigens.
  • Even when responses are made against tumours, immune selection pressure may lead to the outgrowth of cells that have down-regulated or have mutations in proteins required for antigen presentation, e.g. MHC molecules.
  • Development of immunotherapy for tumours is an intensive area of research, but cost of treatment is a major issue.
40
Q

Which factors are important in cancer immunity?

A
  • PD1 and PDL1
  • CTLA4
  • VEGF
  • endothelia B receptor
  • IL4, 10, 13
41
Q

MAGE-3

A
  • Melanoma associated antigens
  • is a cancer testis antigen (silent in normal tissues except in male germ cells and some also expressed in the placenta)
42
Q

CEA

A

carcinoembryonic antigen

-> normally only expressed in foetus/embyro, but over expressed in a wide range of carcinomas

43
Q

HEGFR2

A

human epidermal growth factor receptor 2 (HER2)

-> over expressed in some breast carcinomas

44
Q

Mucin 1 (MUC-1)

A

-> membrane associated glycoprotein, over expressed in very many cancers.

45
Q

PSA, PSMA, PAP

A
  • prostate specific antigen
  • prostate specific membrane antigen
  • prostatic acid phosphatase
46
Q

Death by neglect

A
  • some thymocytes are not positively or negatively selected because they die via neglect before.
  • NB: out of the positively set;ected ones there is some auto reactivity
47
Q

Proof for the immune system attacking tumour associated antigens in healthy tissues

A
  • immunotherapy in mouse caused vitiligo

- pale skin around a melanoma lesion (immune response)

48
Q

T-cell receptor

A
  • alpha-beta

- CD4+ or CD8+ co-receptor

Year 2 - MCD - Immunology (5 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions