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Integrative > Lecture 5: Immuno-Pathology of Cancers > Flashcards

Lecture 5: Immuno-Pathology of Cancers Flashcards

1
Q

What effect do effector immune cells have on cancer cells in the early stages?

A

During the early stages of cancer development, effector immune cells eliminate immunogenic cancer cells

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2
Q

What effect do T-Cells have on cancers?

A
  • In early stages of cancer development, if enough
    immunogenic antigens (tumour antigens) are
    produced, naïve T cells will be primed in the lymph
    nodes
  • They then move to the tumour and mount a
    protective effector immune response
  • Thus eliminating immunogenic cancer cells
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3
Q

What is a high level of T-cell infiltration in cancers is associated with?

A

A favourable prognosis in many cancers (melanoma,
breast, lung, ovarian, colorectal, renal, prostate and
gastric)

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4
Q

What are the most prominent anti-tumour cells?

A

CD8+ T-cells

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5
Q

How do CD8+ exert an efficient anti-tumoral attack?

A
  • Upon priming and activation by APCs
  • The CD8+ T cells differentiate into cytotoxic T
    lymphocytes (CTLs)
  • Through the exocytosis of perforin and granzyme-
    containing granules they launch an anti-tumoral
    attack
  • Resulting in the direct destruction of target cell
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6
Q

What is Cancer Immunoediting?

A
  • Less immunogenic cancer cells escape the immune
    control of T cells and survive,
  • The surviving cancer cells adopt an immuno-
    resistant phenotype
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7
Q

What are the 3 Phases of Cancer Immunoediting?

A
  • Elimination
  • Equilibrium
  • Escape
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8
Q

Throughout the phases of cancer immunoediting how can disease progress?

A

Tumour immunogenicity is edited and immunosuppressive mechanisms that enable disease
progression are acquired

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9
Q

Once the tumours have escaped from initial tumoricidal immunity, they undergo different
strategies that tip the balance toward immune tolerance, what cells play a major role in this?

A

TAMs (tumour-associated macrophages) play a key
role (“hijacking of the immune system”)

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10
Q

What are the characteristics of M1 Macrophages? (5)

A
  • Pro-inflammatory
  • Tumoricidal
  • Antigen presentation capacity
  • Killing of intracellular pathogens
  • Tissue damage
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11
Q

What are the characteristics of M2 Macrophages? (6)

A
  • Anti-inflammatory
  • Tumour promotion
  • Immunoregulation
  • Angiogenesis
  • Tissue Remodelling
  • Matrix deposition
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12
Q

As cancer progresses what happens to M1 macrophages?

A

The TME (tumour microenvironment) including cancer cells, elicits an M2-like polarization of macrophages that is pro-tumourigenic

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13
Q

TAMs (Tumour Associated Macrophages) are though to more closely resemble what types of macrophage?

A

M2

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14
Q

What are the 2 main strategies by which cancer cells evade the immune response?

A
  • Avoiding immune recognition
  • Instigating an immunosuppressive TME
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15
Q

How do cancer cells avoid immune recognition?

A
  • Cancer cells may lose the expression of tumour
    antigens on the cell surface
  • Thus avoiding the recognition by cytotoxic T-cells
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16
Q

How do cancer cells instigate an immunosuppressive TME? (3)

A
  • Secretion of suppressive molecules such as IL-10,
    TGF-β, prostaglandin E2, and VEGF
  • Expression of inhibitory checkpoint molecules such
    as PD-L1 and CTLA-4
  • Induction of the recruitment of TAMs and Tregs by
    tumour derived chemokines (CCL2, CSF1, CCL5,
    CCL22, CXCL5)
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17
Q

What is Cancer Immunotherapy?

A

A therapy used to treat cancer patients that involves or uses components of the immune system

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18
Q

Examples of Cancer Immunotherapies (3)

A
  • Antibodies that bind to and inhibit the function of
    proteins expressed by cancer cells
  • T-cell infusions (CAR T cell Therapy)
  • Vaccines
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19
Q

What are the different mechanisms of Cancer Immunotherapy Monoclonal Antibodies (MABs) used for cancer therapy? (4)

A
  • Blocking proliferative signalling: cetuximab (EGFR),
    trastuzumab (HER2)
  • Delivering drugs or radiation to cancer cells
  • Blocking angiogenic signalling
  • Helping immune system to detect and kill cancer
    cells
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20
Q

What is Trastuzumab?

A

Aka Herceptin is a humanised monoclonal antibody against HER2 receptor

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21
Q

What are the Modes of Action of Trastuzumab? (3)

A
  • Binding to HER2 results in inhibition of downstream
    pathways including MAPK and PI3K/Akt that lead to
    proliferation etc
  • Binding to HER2 results in receptor internalisation
  • Binding to HER2 attracts immune cells to tumour
    site and promotes ADCC
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22
Q

What is Trastuzumab used to treat?

A

Treatment of HER2 positive breast cancer that represent 20-30% of all breast cancers

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23
Q

What is Cetuximab?

A

It is a chimaeric monoclonal antibody against EGFR

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24
Q

What is Cetuximab used to treat? (3)

A
  • Metastatic colorectal cancer
  • Metastatic non-small cell lung cancer
  • Head and neck cancer
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25
Q

What are the Modes of Action of Cetuximab? (3)

A
  • Binding to EGFR competitively inhibits the
    binding of EGF, resulting in prevention of receptor
    dimerization and inhibition of downstream
    pathways leading to proliferation
  • Binding to EGFR resulting in receptor internalisation
    and degradation
  • Binding to EGFR attracts immune cells to tumour
    site and promotes ADCC
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26
Q

What is Bevacizumab?

A

A monoclonal humanised antibody to VEGF (Vascular
Endothelial Growth Factor)

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27
Q

What is Bevacizumab used to treat? (6)

A
  • Colorectal cancer
  • Non small cell lung carcinoma
  • Renal cancer
  • Glioblastoma
  • Ovarian cancer
  • Eye diseases such as macular degeneration
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28
Q

What is the MOA of Bevacizumab?

A

Inhibition of angiogenesis as a result of binding to
VEGF

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29
Q

What are Immune Checkpoint Inhibitors? What checkpoints do they inhibit? (3)

A
  • T cell targeted immunomodulators blocking the
    immune checkpoints
  • PD1, PD-L1 and CTLA-4
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30
Q

What is Ipilimumab?

A

First antibody blocking an immune checkpoint (CTLA4)

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31
Q

What monoclonal antibodies target PD1? (2)

A
  • Pembrolizumab
  • Nivolumab
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32
Q

What monoclonal antibodies target PDL1? (2)

A
  • Atezolizumab
  • Durvalumab
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33
Q

What is done in CAR T-Cell Therapy?

A
  • When a patient’s own T-cells are genetically
    engineered to express a Chimaeric Antigen Receptor
    (CAR) to target cancer cells that express this tumour
    antigen
  • CAR T cells are then expanded for clinical use and
    infused back into the patient’s body
  • They attack and destroy cancer cells that express
    the same tumour antigen
34
Q

What is the main outcome of immune checkpoint PD-L1 inhibition?

A

Activation of CD8+ T-lymphocytes

35
Q

What is the most common type of childhood cancer?

A

Acute Lymphoblastic Leukaemia

36
Q

What is CD19-directed CAR T-cell Therapy used to treat?

A
  • Several large clinical trials have demonstrated
    excellent efficacy for patients with relapsed or
    refractory and paediatric B-cell acute lymphoblastic
    leukaemia (B-ALL)
  • With complete remission (CR) rates as high as 68%
    to 93%
37
Q

What is the problem with CD19-directed CAR T-cell Therapy for acute lymphoblastic leukaemia?

A

Many of these patients will relapse, most often with CD19-negative leukaemia (several mechanisms of
resistance )

38
Q

What are the 2 Classes of Tumour Antigens?

A
  • Tumour specific antigens (TSA)
  • Tumour associated antigens(TAA)
39
Q

What cells are TSA’s presented?

A

Expressed only by cancer cells and not in healthy tissues

40
Q

What cells are TAA’s presented?

A

Antigens with low expression in normal tissues and
over-expression in tumour cells

41
Q

Examples of TSAs (2)

A
  • Mutation-associated neoantigens (MANA)
  • Viral antigens may also represent the target for
    immune recognition of virus-associated tumour
42
Q

What is the role of MANAs?

A

Result from DNA mutation/rearrangement and play a
crucial role in the recognition of tumour cells by
CD8+ T cells after immune checkpoint treatment

43
Q

Examples of TAAs (2)

A
  • HER2
  • Melanocyte differentiation proteins
44
Q

What are characteristics of “Hot” Tumours? (4)

A
  • Inflamed
  • Many mutations
  • High number of T-cells inside the tumour
  • Large presence of PD-1 and PD-L1
45
Q

What cancers are “Hot” Tumours found in? (5)

A
  • Lung
  • Melanoma
  • Liver
  • Bladder
  • Head and Neck
46
Q

What are characteristics of “Cold” Tumours? (4)

A
  • Non-inflamed
  • Fewer mutations
  • Few to no T-cells inside the tumour
  • No PD-1 or PD-L1 protiens
47
Q

What cancers are “Cold” Tumours found in? (2)

A
  • ER+ breast cancer
  • Prostate
48
Q

What are characteristics of “Warm” Tumours? (3)

A
  • Moderate number of mutations
  • T-cells at periphery of the tumour
  • May have PD-1 & PD-L1 proteins
49
Q

What cancers are “Warm” Tumours found in? (5)

A
  • Breast
  • Lung
  • Ovarian
  • Brain
  • Kidney
50
Q

What do HPV Vaccines contain?

A

HPV vaccines contain HPV L1 self-assembling virus-like particles (VLPs) produced by recombinant
technology

51
Q

What are the 2 types of HPV vaccination availible?

A
  • Gardasil, a polyvalent vaccine that protects against
    HPV types 16, 18, 6 and 11
  • Cervarix, a bivalent vaccine that protect against HPV
    types 16 and 18
52
Q

What are Lymphoproliferative Disorders?

A
  • Comprise a heterogeneous group of diseases
    characterised by uncontrolled production of
    lymphocytes
  • This causes monoclonal lymphocytosis, bone
    marrow infiltration & lymphadenopathy
53
Q

What can monoclonal expansion of lymphocytes give rise to? (3)

A
  • Leukaemia
  • Lymphoma
  • Myeloma
54
Q

What is Leukaemia?

A

A group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells

55
Q

Classes of Leukaemia (4)

A
  • Lymphocytic Leukaemia
  • Myeloid Leukaemia
  • Acute Leukaemia
  • Chronic Leukaemia
56
Q

What is Lymphocytic Leukaemia?

A
  • Aka lymphoid or lymphoblastic leukaemia
  • Develops in the white blood cells (lymphocytes) in
    the bone marrow
57
Q

What is Myeloid Leukaemia?

A

Aka myelogenous leukaemia may also start in white blood cells other than lymphocytes, as well as red blood cells and platelets

58
Q

What is Acute Leukaemia?

A

It is rapidly progressing and results in the accumulation of immature, functionless blood cells in the bone marrow

59
Q

What is Chronic Leukaemia?

A

Progresses more slowly and results in the accumulation of relatively mature, but still abnormal, white blood cells

60
Q

What is Acute Lymphoid Leukaemia characterised by?

A

A malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood and extramedullary sites

61
Q

What is seen on histology of Acute Lymphoid Leukaemia?

A

Bone marrow aspirate smears reveal increased
blasts they are:
* Small to medium in size with high nuclear-to-
cytoplasmic ratios
* Round to irregular nuclei
* Smooth chromatin
* Scant basophilic agranular cytoplasm

62
Q

What is Acute myeloid leukaemia (AML) characterised by?

A

By the accumulation of malignant, poorly differentiated myeloid cells within the bone marrow, peripheral blood and infrequently in other organs

63
Q

What is the most common acute leukaemia in
adults?

A

Acute myeloid leukaemia (AML)

64
Q

What is the most common leukaemia in western
countries?

A

Chronic lymphocytic leukaemia (CLL)

65
Q

What cells are seen in Chronic lymphocytic leukaemia (CLL)?

A

Smudge cell

66
Q

What is Chronic lymphocytic leukaemia (CLL) characterised by?

A
  • Clonal proliferation and accumulation of mature,
    typically CD5+ B cells within the blood, bone
    marrow, lymph nodes and spleen
  • CLL is initiated by the loss or addition of large
    amounts of chromosomal material
  • Followed later by additional mutations that may
    render the leukaemia more aggressive
67
Q

What are the most common cytogenetic aberrations in CLL? (4)

A
  • Deletions on the long arm of chromosome 13 (~
    55% of all cases)
  • Deletions of the long arm of chromosome 11
  • Trisomy 12 is observed in 10% to 20% of CLL
    patients
  • Deletions of the short arm of chromosome 17
68
Q

CML accounts for what percentage of newly diagnosed cases of leukaemia in adults?

A

~ 15%

69
Q

CML is characterised by what chromosomal abnormality?

A
  • A balanced chromosomal translocation, t(9;22).
    (q34;q11.2)
  • Involving a fusion of the Abelson gene (ABL1) from
    chromosome 9 with the breakpoint cluster region
    (BCR) gene on chromosome 22
  • Known as the Philadelphia chromosome
70
Q

What oncogene is generated in CML?

A
  • Translocation results in the generation of a BCR
    ABL1 fusion oncogene, that encodes for a BCR-ABL
    oncoprotein
  • A constitutively active tyrosine kinase that promotes
    cellular proliferation
71
Q

How is CML treated?

A

Small molecule tyrosine kinase inhibitors (TKIs) that target and inhibit the function of the BCR-ABL oncoprotein (imatinib, dasatinib)

72
Q

What is Hodgkin Lymphoma (HL) characterised by?

A

Reed-Sternberg Cells

73
Q

How is Hodgkin Lymphoma treated?

A
  • Combination chemotherapy, radiation or combined
    modality treatment
  • Including PD-1 inhibitors Nivolumab and
    Pembrolizumab
74
Q

What is Hodgkin Lymphoma?

A
  • The cancer cells are mature B cells that have
    become malignant
  • Referred to as Hodgkin cells when they are
    mononucleated
  • Reed–Sternberg (HRS) cells when they are large and
    multinucleated
75
Q

What is Non-Hodgkin Lymphoma (NHL)?

A

Heterogenous group of lymphoproliferative malignancies that are much less predictable than HL and have a far greater predilection to metastasise

76
Q

What percentage of NHL are B-cell origin and T-cell origin?

A
  • 80% B cell
  • 20% T cell
77
Q

Major Categories of NHL (3)

A
  • Diffuse large B cell lymphoma (high grade, most
    common): BCL6 translocations
  • Follicular lymphoma (low grade, mostly adults):
    BCL2/IGH translocations
  • Burkitt’s lymphoma (high grade, mostly children):
    Myc/IGH translocations
78
Q

What is Multiple Myeloma?

A
  • Malignancy of terminally differentiated plasma
    cells
  • Patients typically present with bone marrow
    infiltration of clonal plasma cells and monoclonal
    protein in the serum and/or urine
79
Q

What are primary genetic events in the development of Multiple Myeloma?

A

Chromosomal translocations involving the
immunoglobulin heavy-chain genes (IGH) and
aneuploidy

80
Q

How is Multiple Myeloma treated? (6)

A
  • Proteasome inhibitors (bortezomib,
    carfilzomib)
  • Immunomodulatory drugs
  • Corticosteroids
  • Alkylating agents
  • Anthracyclines
  • Autologous haemopoietic stem cell transplantation
81
Q
A

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