Lecture 5: Immuno-Pathology of Cancers Flashcards
(81 cards)
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
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
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)
4
Q
What are the most prominent anti-tumour cells?
A
CD8+ T-cells
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
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
7
Q
What are the 3 Phases of Cancer Immunoediting?
A
- Elimination
- Equilibrium
- Escape
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
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”)
10
Q
What are the characteristics of M1 Macrophages? (5)
A
- Pro-inflammatory
- Tumoricidal
- Antigen presentation capacity
- Killing of intracellular pathogens
- Tissue damage
11
Q
What are the characteristics of M2 Macrophages? (6)
A
- Anti-inflammatory
- Tumour promotion
- Immunoregulation
- Angiogenesis
- Tissue Remodelling
- Matrix deposition
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
13
Q
TAMs (Tumour Associated Macrophages) are though to more closely resemble what types of macrophage?
A
M2
14
Q
What are the 2 main strategies by which cancer cells evade the immune response?
A
- Avoiding immune recognition
- Instigating an immunosuppressive TME
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
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)
17
Q
What is Cancer Immunotherapy?
A
A therapy used to treat cancer patients that involves or uses components of the immune system
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
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
20
Q
What is Trastuzumab?
A
Aka Herceptin is a humanised monoclonal antibody against HER2 receptor
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
22
Q
What is Trastuzumab used to treat?
A
Treatment of HER2 positive breast cancer that represent 20-30% of all breast cancers
23
Q
What is Cetuximab?
A
It is a chimaeric monoclonal antibody against EGFR
24
Q
What is Cetuximab used to treat? (3)
A
- Metastatic colorectal cancer
- Metastatic non-small cell lung cancer
- Head and neck cancer
25
What are the Modes of Action of Cetuximab? (3)
* 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
26
What is Bevacizumab?
A monoclonal humanised antibody to VEGF (Vascular
Endothelial Growth Factor)
27
What is Bevacizumab used to treat? (6)
* Colorectal cancer
* Non small cell lung carcinoma
* Renal cancer
* Glioblastoma
* Ovarian cancer
* Eye diseases such as macular degeneration
28
What is the MOA of Bevacizumab?
Inhibition of angiogenesis as a result of binding to
VEGF
29
What are Immune Checkpoint Inhibitors? What checkpoints do they inhibit? (3)
* T cell targeted immunomodulators blocking the
immune checkpoints
* PD1, PD-L1 and CTLA-4
30
What is Ipilimumab?
First antibody blocking an immune checkpoint (CTLA4)
31
What monoclonal antibodies target PD1? (2)
* Pembrolizumab
* Nivolumab
32
What monoclonal antibodies target PDL1? (2)
* Atezolizumab
* Durvalumab
33
What is done in CAR T-Cell Therapy?
* 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
What is the main outcome of immune checkpoint PD-L1 inhibition?
Activation of CD8+ T-lymphocytes
35
What is the most common type of childhood cancer?
Acute Lymphoblastic Leukaemia
36
What is CD19-directed CAR T-cell Therapy used to treat?
* 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
What is the problem with CD19-directed CAR T-cell Therapy for acute lymphoblastic leukaemia?
Many of these patients will relapse, most often with CD19-negative leukaemia (several mechanisms of
resistance )
38
What are the 2 Classes of Tumour Antigens?
* Tumour specific antigens (TSA)
* Tumour associated antigens(TAA)
39
What cells are TSA's presented?
Expressed only by cancer cells and not in healthy tissues
40
What cells are TAA's presented?
Antigens with low expression in normal tissues and
over-expression in tumour cells
41
Examples of TSAs (2)
* Mutation-associated neoantigens (MANA)
* Viral antigens may also represent the target for
immune recognition of virus-associated tumour
42
What is the role of MANAs?
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
Examples of TAAs (2)
* HER2
* Melanocyte differentiation proteins
44
What are characteristics of "Hot" Tumours? (4)
* Inflamed
* Many mutations
* High number of T-cells inside the tumour
* Large presence of PD-1 and PD-L1
45
What cancers are "Hot" Tumours found in? (5)
* Lung
* Melanoma
* Liver
* Bladder
* Head and Neck
46
What are characteristics of "Cold" Tumours? (4)
* Non-inflamed
* Fewer mutations
* Few to no T-cells inside the tumour
* No PD-1 or PD-L1 protiens
47
What cancers are "Cold" Tumours found in? (2)
* ER+ breast cancer
* Prostate
48
What are characteristics of "Warm" Tumours? (3)
* Moderate number of mutations
* T-cells at periphery of the tumour
* May have PD-1 & PD-L1 proteins
49
What cancers are "Warm" Tumours found in? (5)
* Breast
* Lung
* Ovarian
* Brain
* Kidney
50
What do HPV Vaccines contain?
HPV vaccines contain HPV L1 self-assembling virus-like particles (VLPs) produced by recombinant
technology
51
What are the 2 types of HPV vaccination availible?
* 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
What are Lymphoproliferative Disorders?
* Comprise a heterogeneous group of diseases
characterised by uncontrolled production of
lymphocytes
* This causes monoclonal lymphocytosis, bone
marrow infiltration & lymphadenopathy
53
What can monoclonal expansion of lymphocytes give rise to? (3)
* Leukaemia
* Lymphoma
* Myeloma
54
What is Leukaemia?
A group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells
55
Classes of Leukaemia (4)
* Lymphocytic Leukaemia
* Myeloid Leukaemia
* Acute Leukaemia
* Chronic Leukaemia
56
What is Lymphocytic Leukaemia?
* Aka lymphoid or lymphoblastic leukaemia
* Develops in the white blood cells (lymphocytes) in
the bone marrow
57
What is Myeloid Leukaemia?
Aka myelogenous leukaemia may also start in white blood cells other than lymphocytes, as well as red blood cells and platelets
58
What is Acute Leukaemia?
It is rapidly progressing and results in the accumulation of immature, functionless blood cells in the bone marrow
59
What is Chronic Leukaemia?
Progresses more slowly and results in the accumulation of relatively mature, but still abnormal, white blood cells
60
What is Acute Lymphoid Leukaemia characterised by?
A malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood and extramedullary sites
61
What is seen on histology of Acute Lymphoid Leukaemia?
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
What is Acute myeloid leukaemia (AML) characterised by?
By the accumulation of malignant, poorly differentiated myeloid cells within the bone marrow, peripheral blood and infrequently in other organs
63
What is the most common acute leukaemia in
adults?
Acute myeloid leukaemia (AML)
64
What is the most common leukaemia in western
countries?
Chronic lymphocytic leukaemia (CLL)
65
What cells are seen in Chronic lymphocytic leukaemia (CLL)?
Smudge cell
66
What is Chronic lymphocytic leukaemia (CLL) characterised by?
* 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
What are the most common cytogenetic aberrations in CLL? (4)
* 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
CML accounts for what percentage of newly diagnosed cases of leukaemia in adults?
~ 15%
69
CML is characterised by what chromosomal abnormality?
* 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
What oncogene is generated in CML?
* 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
How is CML treated?
Small molecule tyrosine kinase inhibitors (TKIs) that target and inhibit the function of the BCR-ABL oncoprotein (imatinib, dasatinib)
72
What is Hodgkin Lymphoma (HL) characterised by?
Reed-Sternberg Cells
73
How is Hodgkin Lymphoma treated?
* Combination chemotherapy, radiation or combined
modality treatment
* Including PD-1 inhibitors Nivolumab and
Pembrolizumab
74
What is Hodgkin Lymphoma?
* 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
What is Non-Hodgkin Lymphoma (NHL)?
Heterogenous group of lymphoproliferative malignancies that are much less predictable than HL and have a far greater predilection to metastasise
76
What percentage of NHL are B-cell origin and T-cell origin?
* 80% B cell
* 20% T cell
77
Major Categories of NHL (3)
* 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
What is Multiple Myeloma?
* 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
What are primary genetic events in the development of Multiple Myeloma?
Chromosomal translocations involving the
immunoglobulin heavy-chain genes (IGH) and
aneuploidy
80
How is Multiple Myeloma treated? (6)
* Proteasome inhibitors (bortezomib,
carfilzomib)
* Immunomodulatory drugs
* Corticosteroids
* Alkylating agents
* Anthracyclines
* Autologous haemopoietic stem cell transplantation
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