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Cancer Biology > CBIO7: Cancer Immunotherapy > Flashcards

CBIO7: Cancer Immunotherapy Flashcards

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1
Q

What are the learning outcome?

A

LO1: Recognise the general concept of cancer immunobiology
LO2: Describe tumour antigens expressed on cancer cells.
LO3: Explain how viruses can cause cancer.
LO4: Describe how the immune system mounts an immune response against tumours
LO5: Recognise how tumours evade immunity.

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2
Q

Define aneuploidy

A

Variation in chromosome number in a cell, i.e. in humans, anything other than 46 chromosomes

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3
Q

Define antigen

A

A molecule expressed on the surface of cells, viruses or bacteria that can be recognized by the immune system and triggers its response

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4
Q

Define Cytokines

A

They are proteins that mediate communication between cells. Some of them, such as interferon and interleukin, are important for immune system regulation

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5
Q

Define G-protein coupled receptors

A

A family of receptors that recognize specific molecules outside the cell (called G-proteins), which trigger cellular responses via the activation of internal signal transduction pathways

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6
Q

Define Genetic amplification

A

An increased number of copies of a specific gene

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7
Q

Define Glycosylation

A

It is a post-translational modification by which a carbohydrate, or glycan, is added to a noncarbohydrate structure, typically a protein or a lipid

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8
Q

Define Immune checkpoints

A

Key regulators of the immune system that can prevent the overactivation of the immune response by regulating the length and intensity of T-cell activity

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9
Q

Define Immunogenicity

A

The ability of a substance (typically an antigen) to trigger an immune response

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10
Q

Define Immunosuppressive

A

A condition in which the immune system activity is reduced, decreasing its ability to protect the body against infections and disease

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11
Q

Define Major histocompatibility complex (MHC)

A

A set of proteins present on the surface of many cells (typically APC) that stimulate the interaction between normal cells and immune cells

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12
Q

Define Memory cells

A

T-cells and B-cells that “remember” specific antigens they have interacted with during the immune response and can rapidly proliferate upon subsequent exposure, generating a rapid response

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13
Q

Define Mutation

A

Permanent modification of the genome sequence

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14
Q

Define Nude mice

A

They are mice that have been genetically modified to have an inhibited immune system, lack of thymus resulting in reduced T-cells

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15
Q

Define Oncofetal Antigens

A

Antigens expressed in certain types of tumours that are not expressed in normal adult tissues. They are typically present in normal tissues only during fetal development

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16
Q

Define PD-1 (programmed cell death-1)

A

A cell surface protein, part of the PD-1/PD-L1 checkpoint pathway that, upon interaction with PD-1 or PD-2 ligand (PD-L1 or PD-L2), prevents T-cells from attacking the cell expressing it

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17
Q

Define Polyomavirus

A

A small virus , lacking an envelope, whose genetic material is a circular double-stranded DNA of around 3kb. Polyomaviruses have been identified in birds and mammals

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18
Q

Define P53

A

It is a protein that in response to specific stimuli (such as DNA damage) induces apoptosis, cell cycle arrest, or senescence. It is dysfunctional in many cancer

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19
Q

Define Retinoblastoma protein (pRb)

A

A tumour suppressor protein that normallyinhibits cell cycle progression and therefore prevents cell growth

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20
Q

Define Retrovirus

A

It is a virus whose genetic material is RNA that, upon infection of a cell, is reverse-transcribed into DNA and integrated into the host genome where it becomes functional

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21
Q

Define T-cell receptors (TCRs)

A

A set of proteins present on the surface of T-cells. The first signal necessary to activate T-cells, is interaction of TCRs with MHC components on Antigen-presenting cells

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22
Q

What are the 5 pillars of cancer therapy

A

1) Surgery
2) Radiotherapy
3) Targeted therapy
4) Chemotherapy
5) Immunotherapy

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23
Q

Explain Radiotherapy

A

(radiation or x- ray therapy) used high energy radiation to destroy cancer cells or impede their growth. Usually beamed through the skin, it can also be administered internally by placing small sourced of radioactive material in or near the cancer

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24
Q

Explain Surgery

A

remains the optimum treatment for early, localised cancer. It is often used in combination with radiotherapy and/or chemotherapy to try and mop up any cancer cells remaining in the body

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25
Q

Explain Targeted therapy

A

Targeted therapy or personalised medicine targets specif mutations in cancer cells. This is usually done with small-molecule drugs that enter cells or with monoclonal antibodies that attach to specific targets outside the cell

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26
Q

Explain Chemotherapy

A

Chemotherapy is usually used in combination with other treatments; it is not curative for most solid cancers when used alone. Cancers which rely on particulate hormones to grow can often be controlled by drugs that suppress the hormones or block their effect

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27
Q

Explain Immunotherapy

A

Immunotherapy is a drug treatment that empowers the body’s immune system to attack cancer. Made up of special cells, chemicals and organs, the immune system protects the body from infection

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28
Q

How would you demonstrate the existence of tumour antigens?

A

One way could be by transplanting tumour cells in mice and seeing if the immune system responds to them: Immune cells responded to a tumour that was injected (grafted) into a mouse that had previously been immunised with inactivated cells from the same tumour. However, they did not prevent the tumour growth when injecting a different tumour, i.e. with different antigens

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29
Q

What are the three types of cancer?

A

Tumour-specific antigens (TSAs)
Tumour-associated antigens (TAAs)
Oncofetal antigens

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30
Q

What the different ways tumour antigens can be expressed, compared to normal cells?

A
  1. Tumour-specific antigens (TSAs) - These are present only on tumour cells, and not present on normal cells
  2. Tumour-associated antigens (TAAs) - These can be expressed at high levels on tumour cells, but are not exclusive to them - they can be normally expressed at low levels on normal cells.
  3. Oncofetal antigens - These are inappropriately expressed in tumour cells, and on normal cells only during fetal development. During that time, they are not recognized as “self” because the immune response is still immature.
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31
Q

How do tumours develop specific antigens?

A

Either by acquisition of new mutations or by expression of oncogenic viral proteins.

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32
Q

Explain how tumours develop specific antigens by mutation?

A

Mutations in the DNA of normal cells (e.g. by the action of radiation or chemical carcinogens) can result in modified proteins. Those proteins are then processed in the cytoplasm and can give rise to novel peptides i.e. tumour antigens, which could induce a cell-mediated immune response by cytotoxic T-cells (CTLs).

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33
Q

Explain how tumours develop specific antigens by oncogenic viral proteins? (TSA)

A

Oncogenic viral proteins: Many oncoviruses contain genes that can generate neoplastic transformation of the host cell (viral oncogenes). These genes may either be immediately expressed in the infected cell or integreted into its DNA and expressed afterwards.

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34
Q

What are viral induced tumours? (TSA)

A

Virus-induced tumours are tumours which express the cell surface antigens induced or encoded by the virus. These are common to all tumours associated with that virus. We will elaborate more on this topic later.

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35
Q

What are chemically induced tumours? (TSA)

A

Chemically-induced tumours, on the other hand, express heterogeneous cell surface antigens. Thus, tumours induced by the same chemical, do not tend to share the same tumour specific antigens.

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36
Q

How can you discriminate between antigens of tumours and normal cells if they share the same antigens?

A

Tumours might express different levels of these antigens or might modify them after translation.

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37
Q

By what processes can you determine the difference between tumour and normal cell antigens?

A

1) Amplification (overexpression) of a molecule can be caused by DNA alterations/mutations, viral infection or genetic disorders.
2) Glycosylation is a process that attaches a carbohydrate to a target protein or other organic molecule. Glycosylation is altered in many tumours.

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38
Q

What are oncofetal antigens?

A

They are antigens that are normally not expressed, or are poorly expressed, in adult life but are present during fetal development

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39
Q

Give two examples of oncofetal antigens, where are they expressed?

A
  • Carcinoembryonic antigen (CEA) colon cancer cells and other epithelial tumours
  • α-fetoprotein (AFP) liver cancer cells

They can be used as tumour markers.

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40
Q

Is Mesothelin a TSA or TAA?

A

TAA

41
Q

Is mutated KRAS a TSA or TAA?

A

TSA

42
Q

Is HPV E6 and E7 a TSA or TAA?

A

TSA

43
Q

Is CD19 a TSA or TAA?

A

TAA

44
Q

Give an example of a TAA that is a useful target therapy, and name the cancer

A

ErbB2 -> used to target breast cancer

45
Q

What are the three ways viruses can cause cancer?

A

1) They may cause chronic inflammation. Inflammation arises when the immune system attacks the virus, so it is protective. However, chronic inflammation causes increased cell division - making cells to replace damaged cells. Whenever cells divide, especially rapidly, genetic mutation may arise as a consequence, eventually leading to cancer.
2) They can damage DNA directly.
3) They may alter the ability of the immune system to fight off cancer cells.

46
Q

What are the two types of oncoviruses you can have?d

A

DNA or RNA viruses

47
Q

How do oncoviruses function?

A

They integrate their DNA into the host cell’s genome causing oncogenic transformation of the infected cell

48
Q

What is the life cycle of DNA oncoviruses?

A

Entry into the cell and uncoating of the DNA, when the host cell is in S phase viral DNA is release and the virus uses host enzymes for viral transcription and replication, before translation of the viral protein coat and DNA which is then reassmbled and progeny virus particles are released from the cell to infect other cells

49
Q

Discuss HPV

A

Papillomaviruses are small DNA viruses (genome size is roughly 8 kb). Around 60 different HPV strains have been identified. HPV infection can result in both benign tumours (such as warts) and malignant tumours

50
Q

Name some malignant tumours and their prevelances

A

Vaginal cancer - 75% are caused by HPV
Head and neck cancer - 72% are related to HPV
Anal cancer - 91% are due to HPV
Cervical cancer - almost all are related to high-risk strains of HPV
Penile cancer - 63% are caused by HPV
Vulvar cancer - 35% are related to HPV `

51
Q

In persistent infection, what happens to the HPV genome?

A

It is integrated into that of the host cell. The expression of two HPV early-stage genes, E6 and E7 induces cell transformation.

52
Q

How do the HPV proteins E6 and E7 cause cancer?

A

by interfering with the function of the host cell’s Retinoblastoma protein (pRb) and p53 protein: which provokes uncontrolled cell proliferation. E7 binds to and inactivates the tumour suppressor pRb, while E6 stimulates ubiquitin-mediated degradation of p53, which stimulates replication and cell-division.

53
Q

How can the HPV remain hidden from the immune system?

A

HPV virus often does not cause a significant immune response and therefore can remain hidden from the immune system.

54
Q

Briefly discuss Hepatitis B and cancer

A

The hepatitis B viruses have very small genomes (roughly 3 kb) and tend to infect liver cells, which generally results in acute liver damage.

55
Q

In 5 to 10% cases of hepatitis B infection a chronic infection of the liver develops,

A

It is associated with a massive increase (100-fold) in risk of liver cancer

56
Q

Which gene in hepatitis B viral genome mediates cell transformation by driving abnormal cell proliferation and survival? How does it work?

A

X gene

It does this by hijacking expression of cellular genes

57
Q

Briefly discuss Epstein-Barr Virus (EBV) and cancer?

A

Although the Epstein-Barr virus is best known for causing mononucleosis (“kissing disease”), it is also linked with the development of other types of lymphoma

58
Q

What lymphomas is EBV linked to the development of?

A

Hodgkin’s lymphoma – in around 50% of cases
Burkitt’s lymphoma – a highly aggressive form of non-Hodgkin’s lymphoma
HIV-associated lymphoma.
Post-transplant lymphoma – almost always associated with EBV infection

59
Q

The ability of HHV-8 to cause Kaposi sarcoma is The ability of HHV-8 to cause Kaposi sarcoma is increased in people with what?

A

a compromised immune system

60
Q

How does HHV-8 cause Kaposi sarcoma?

A

It involves a combination of viral proteins promoting survival, proliferation and transformation, together with the establishment of a paracrine mechanism between viral cytokines and the viral G-protein coupled receptor (vGPCR).

61
Q

What pathways are affected by HHV-8?

A
  • Immune modulation
  • Apoptosis Regulation
  • Proliferation
  • Genetic Insability
62
Q

What is the only polyomavirus associated with human cancer?

A

Merkle cell polyomavirus (MCPyV)

63
Q

What can MCPyV infection provoke?

A

Merkel cell carcinoma, which is a lethal skin cancer

64
Q

What do MCPyV oncoproteins promote?

A

Neoplastic transformation through interaction with host proteins including pRb and p53

65
Q

Name DNA viruses

A 
Human papillomavirus (HPV)
Hepatitis B
Epstein-Barr Virus (EBV) 
Human herpes virus 8 (HHV-8) 
Merkel cell polyomavirus
66
Q

Name RNA viruses

A

Hepatitis C
T-Lymphotropic Virus (HTLV-1)
Human Immunodeficiency Virus (HIV)

67
Q

Briefly describe Hepatitis C

A

Hepatitis C virus (HCV) infection is also associated with the risk of developing liver cancer. Roughly 80% of people infected with HCV develop a chronic infection (this is in contrast to hepatitis B, which does not usually cause chronic infection).

68
Q

Why does cancer arise from, hepatitis C?

A

Indirectly: HCV are that liver cells keep on multiplying to compensate the loss of cells constantly killed by the virus, and also by the immune cells (to stop the virus spreading). This continuous turnover of liver cells results in accumulation of random DNA mutations in cells that can be oncogenic.

69
Q

Briefly describe T-Lymphotropic Virus (HTLV-1) and cancer

A

HTLV-1 is a retrovirus that can promote T-cell leukaemia. Products of the viral genes Tax and HBZ provoke the neoplastic transformation of T lymphocytes, by affecting the expression of several genes controlling cellular processes

70
Q

What pathways are affected by HLV-1 that lead to the production of cancerous cells:

A

1) Cell cycle and maintenance of genomic integrity.
2) DNA repair pathways, leading to mutations in DNA.
3) aneuploidy (abnormal chromosome numbers), which is a possible cause of transformation (normal cells becoming cancer cells)

71
Q

How does an HTLV-1 infected cell become leukemic?

A

Genetic and epigenetic abnormalities, over long-term latency:

1) Transcriptional abnormalities
2) Inhibition of DNA repair
3) Genomic Instability
4) Signalling deregulation
5) Cell cycle disorder

72
Q

What does HIV attack?

A

Immune system - specifically, T cells

73
Q

What effect does this do to the human body?

A

Impairs the immune response’s ability to defeat other viral infections that can promote cancer development

74
Q

What viruses are linked to cancer in HIV-infected people?

A 
KSHV
HCV
EBV
Hepatitis B virus (HBV) 
Human papillomaviruses (HPVs)
75
Q

What cancers are linked to HIV infection?

A 
Kaposi's Sarcoma
non-Hodgkin's lymphoma
cervical cancer
Hodgkin's lymphoma
liver cancer
anal cancer
76
Q

How does HIV contribute to cancer?

A

Attacking the host immune system

77
Q

What is the immune system?

A

The immune system is the main defence against infectious diseases. It recognises and tries to remove anything in our body that is unfamiliar. It is very good at destroying pathogens (bacteria and viruses) but what about cancer?

78
Q

What is the theory of immune surveillance describing?

A

a theory describing how the immunity not only protects us from infectious agents but also recognizes and destroys abnormal/mutated cells.

79
Q

What did Paul Ehrich hypothesise?

A

that our immune response continuously reacts against cancer cells as fast as they appear in our bodies.

80
Q

What did Lewis Thomas suggest?

A

that the immune system recognizes newly arising tumours through the expression of tumour specific neo-antigens on tumour cells and eliminates them, maintaining tissue homeostasis in complex multicellular organisms

81
Q

Give three pieces of evidence supporting the immune surveillance theory

A
  • Patients on immunosuppressive medications after transplants show higher occurrence of Epstein-Barr virus–positive (EBV+) large B-cell lymphomas.
  • Patients with AIDS (i.e. HIV-infected) exhibit higher occurrence of Kaposi’s sarcoma and EBV+ B cell lymphomas.
  • Young and old people have an increased occurrence of tumours. They often have an immune system that is less effective.
82
Q

Give two pieces of evidence not supporting the immune surveillance theory

A
  • Mice lacking thymus and T cells (called “nude” mice) do not develop cancer.
  • Patients on immunosuppressive medications exhibit higher occurrence of some cancers, but not other common cancers (e.g. breast, lung and colon cancer).
83
Q

What are the two assumptions of the immune surveillance theory?

A

1) This theory assumes that there is only qualitative difference between antigens expressed in cancer and normal cells.
2) It also assumes that cancerous cells develop only when the immune system is impaired, or if cancer cells lose their immunogenicity (the ability to provoke an immune response), enabling them to escape immune surveillance.

84
Q

What are the two main cells involved in tumour response?

A

Professional Antigen Presenting Cells (APC)

T cells

85
Q

What are professional APCs function?

A

They are very efficient at internalizing tumour antigens by phagocytosis, processing them into peptide fragments and then displaying those peptides, bound to a major histocompatibility complex (MHC) molecule, on their surface membrane.

86
Q

What is the first and second signal required for T-cells to attack cancer cells

A

1) An interaction between the MHC and the receptor on the T-cell (TCR).
2) The interaction between co-stimulatory molecules present on the surface membrane of T-cells and APC.

A well-known example is that between CD28, which is present on T cells, and CD80 (also known as B7.1) and CD86 (B7.2), which are expressed on APC.

87
Q

Which are the most common professional antigen-presenting cells?

A

Dendritic cells (DC)
macrophages
B cells

88
Q

What is T-cell’s function?

A

These are activated by APCs to identify and remove cells expressing foreign antigens.

89
Q

What are the main groups of T-cells?

A

Helper T cells

Cytotoxic T lymphocytes (CTL)

90
Q

Explain CTL-mediated killing of tumour cells

A

1) Immature CTLs becomes activated upon recognizing the antigen-MHC class complex (Class I MHC molecules)
2) Most of the activated T cells will expand but some will become memory T cells, which can mount a faster and stronger immune response at a second encounter with the tumour
3) Activated CTLs will destroy target cells and will die when they have done their job.

91
Q

What does tumour immune editing refer to?

A

Changes in tumour immunogenicity, as a consequence of the immune response to cancer, which results in the development of immune-resistance in the tumour

92
Q

What are the 3 stages of immune editing?

A

Elimination/immune surveillance
Equilibrium
Escape

93
Q

Describe the elimination stage of immune editing?

A

The elimination phase of tumour immune editing is described in section 4 (the theory of tumour immune surveillance). There you learnt how the immune system identifies and eliminates tumour cells.

94
Q

Describe the equilibrium stage of immune editing?

A

Equilibrium occurs if some cancer cells were not eradicated in the elimination phase. This is a transitory phase where the immune system and developing tumour are in a balanced state that can last for several years. The tumour cells can remain dormant, or continue acquiring genome modifications that can alter tumour-specific antigens, making them unrecognisable by the immune system.

95
Q

What is the escape phase of immunoediting? When does it occur?

A

This occurs when the immune system is unable to restrict tumour growth, and the cancer cells can begin to grow and expand uncontrollably. Tumour escape has been a major problem in cancer therapy and it has been held responsible for the failure of many immune interventions in cancer.

96
Q

What is the role of Immune checkpoints?

A

Generally function to prevent autoimmunity

97
Q

Give an example of a checkpoint functioning to prevent autoimmunity

A

the PD-1 receptor found on T cells that requires the PD-L1 protein on healthy cells to inhibit the T cell killing the cell. This allows tumour cells with PD-L1 to escape the immune response.

98
Q

Give an example of an anti-tumour strategy

A

blocking immune checkpoints – including using Anti-PD-1 and anti-PD-L1 antibodies to increase tumour cell death

99
Q

When can tumour escape occur?

A
  • Tumour cells may fail to produce tumour antigens
  • Tumour cells might have mutations in MHC so cannot process antigens
  • Tumour cells might produce immunosuppressive cytokines

Cancer Biology (10 decks)

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