Tumour Immunology

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Tumour Immunology Immunotherapy
Dr Usama ALAlami
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Introduction
Cancer Uncontrolled cell growth, division and
proliferation
Malignant transformation due to
1 Chemical or physical carcinogens
Alkylating agents directly mutagenic
Alkylating agent converts into potent mutagens in
vivo
UV and ionizing radiation area also potent
carcinogens
Result in chromosome breakage
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2 Virus-Induced Transformation
First evidence came from Payton Rous in 1910
Cell-free filtrates of chicken sarcoma injected
into healthy chicken
This resulted in sarcoma formation in the healthy
chickens
Filtrate contained RNA virus
Example of a DNA virus related to tumour is the
Epstein-Barr virus (EBV)
Other DNA viruses include hepatitis B (liver
cancer) and papilloma virus (cervical cancer)
RNA viruses (retroviruses) including HIV-1 ?
Kaposis sarcoma
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Other RNA viruses include human T-cell leukaemia
virus type I (HTLV-1) associated with adult T
cell leukaemia
HTLV-2 and 5 are associated with hairy cell
leukaemia and cutaneous T cell leukaemia
respectively.
Oncogenes
Oncogenes may not be unique to transforming
viruses
Oncogenes may also be found in normal cells
The cellular ones in contrast to the viral ones
are called PROTO-ONCOGENES
60-100 different proto-oncogenes have been
identified
These are well conserved amongst species
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Functions Of Proto-Oncogenes
Proto-oncogenes expressed at low levels
Help control cell growth and differentiation
However, abnormal expression in the absence of
external stimuli leads to malignant
transformation
1 Growth Factors
Growth factors bind to their specific receptors
to stimulate or inhibit cell growth
Example is sis proto-oncogene
sis codes for platelet-derived growth factor
(PDGF)
PDGF promotes growth by advancing cells through
the G0 phase of the cell cycle
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Other growth factors include insulin-like growth
factor (IGF)
IGF helps in progression through the G1 phase of
the cell cycle
Inhibitory growth factors include transforming
growth factor ? (TGF- ?) (inhibit progression
through G1 phase of the cell cycle)
2 Growth Factor Receptors
Second group of proto-oncogenes encode growth
factor receptors
Growth factor receptors link information from the
extracellular environment to the intracellular
pathways
Most important growth factor receptors are the
steroid receptors and haemopoiesis growth factor
receptors
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Growth Factor Receptors
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3 Signal Transduction
Help in the tyrosine phosphorylation signal
transduction inside the cell
Examples include the ras family (K, N, and H ras)
4 Transcription Factors
Work at the gene expression level
Example myc
Myc codes for a DNA-binding protein that promotes
proliferation
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Oncogenes What Goes Wrong?
Mutations responsible for oncogene overexpression
In Burkitts lymphoma, c-myc is translocated from
chromosome 8 to chromosome 14.
This results in overexpression of c-myc ?
transcriptional activation
Single point mutations in c-ras detected in lung,
prostate and bladder carcinomas and in
neuroblastoma
Retroviruses may not carry oncogenes but still be
able to transform B cells into lymphomas
Avial leukosis virus (ALV) integrates near the
c-myc proto-oncogene and increases its expression
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Increased TGF-? expression was detected in breast
cancer
Tamoxifen works by inhibiting TGF-? expression
Tumour Suppressor Genes
Induction of cancer also involves deactivation of
TUMOUR SUPPRESSOR GENES
Examples of tumour suppressor genes deactivation
include deactivation of the retinoblastoma gene
(Rb) and p53
Rb and p53 mutation evident in breast cancer,
retinoblastoma and many other types of tumour
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Oncogenes And Programmed Cell Death
Oncogenes result in programmed cell death
APOPTOSIS
Bcl-2 antiapoptosis gene
Isolated from chromosomal translocation in B-cell
follicular lymphomas
Bad another gene that could however promote
cell death and oppose the effects of bcl-2
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Tumours Of The Immune System
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Lymphomas
Proliferate as solid tumours within lymphoid
tissue (e.g. bone marrow, lymph node, thymus)
Examples of lymphomas are Hodgkins and
non-Hodgkins lymphoma
Leukaemias
Proliferate as single cell
Detected by increased cell number in blood or
lymph
Develop in lymphoid or myeloid lineages
Acute or chronic according to clinical
progression of the disease
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Tumour Antigens
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Tumour Antigens
TSA Unique to tumours and do not occur on other
cells
TAA Expressed on normal cells as well
TAA may have increased expression in tumours
Tumour antigens whether TAA or TSA must be
capable of inducing a humoral or cell-mediated
response
Most tumour antigens however elicit a
cell-mediated response
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TSA
Very difficult to detect
Because immune response to such tumours
eliminates all tumour cells bearing recognisable
antigens
TAA
May be expressed on foetal cells, but not adult
cells
Therefore, if they appear later on cancer cells,
the immune system recognises them as non-self
Alternatively, may have higher expression in
tumour cells (e.g. products of oncogenes)
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TAA Continued
e.g. neu oncogene is increased in breast cancer.
Therefore, anti-neu monoclonal antibodies
recognise breast cancer cells and eliminate them
Differences may also be in quality rather than
quantity (e.g. point mutations in ras)
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Immune Response To Tumours
1 Role of Cytotoxic T Lymphocytes (CTL)
Tumour antigens associate with MHCI molecule on
surface of tumours
CTL recognise tumour cells with MHCI
Bind to them and release TNF-? ? toxicity to
tumour cell ? tumour cell killing
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2 Natural Killer Cells (NK Cells)
NK cells Lymphocyte subset capable of lysing a
wide variety of tumour cells
Antibodies coat the tumour cell
NK cells recognise this and attack the tumour
cell Antibody-Dependent Cell-Mediated
Cytotoxicity (ADCC)
NK cells release TNF-? NK cytotxic factor
Chediak-Higashi syndrome ? NK cell impairment ?
increased incidence of certain types of tumour
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3 Macrophages
Activated macrophages secrete lytic enzymes
Also secrete TNF-? ? tumour necrosis
Secrete nitric oxide (potential antitumour
effects)
4 Humoral Antibodies
Help activate complement system
ADCC
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Immune Surveillance Theory
Cancer cells frequently arise
However, eliminated by the immune system
Tumours arise only if cancer cells are able to
escape (evade) this immune surveillance
Evasion Of Immune System
1) Immunologic Enhancement Of Tumour Growth
Antibodies bind to tumour antigens and MASK them
from the CTL
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2) Reduction Of MHCI On Tumour Cells
CTL only recognise antigen in association with
MHCI
Tumour cells are clever and DOWNREGULATE
EXPRESSION OF MHCI
Therefore, less effective presentation to CTL
less effective cell-mediated immune response
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Cancer Immunotherapy
1) Immune Adjuvants
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2) Cytokine Therapy
Genetically-cloned interferons (IFN) IFN-?, ? and
? and IL-1 and 2
IFN-? Treat leukaemia, Kaposis sarcoma, renal
carcinoma and breast carcinoma
IFN- ? increases MHCI expression on tumour cells
increases macrophage activation
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Reading
Janis Kuby (1994). Immunology. 2nd edition.
W.H.Freeman an Company. Chapter 25