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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 Kaposi’s 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
Proto-oncogenes Growth Factor Receptor
fms CSF-1 receptor
erbB EGFR
neu Protein related to EGF receptor
erbA Thyroid hormone receptor
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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 Burkitt’s 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
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
Tumour Suppressor Genes
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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
L e u kae m ias L ym p ho m as
Tum ours of the im m une system
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Lymphomas
Proliferate as solid tumours within lymphoid tissue (e.g. bone marrow, lymph node, thymus)
Examples of lymphomas are Hodgkin’s and non-Hodgkin’s lymphoma
LeukaemiasProliferate 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
T u m ou r-a sso c ia te a n tig e n s (T A A ) T u m o u r-sp e c if ic a n tig e ns (T S A )
Tum our 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
In c re ase ce ll-m e d ia te d im m u n ity
In c re ase h e lp e r T lym p h o cyte (T h) a c tiva tion
In c re ase in te rle uk in -1 (IL -1 ) se cre tion
A c tiva te m a cro p ha g es
Bacteria l a juvants
1) Immune Adjuvants
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2) Cytokine Therapy
Genetically-cloned interferons (IFN) IFN-, and and IL-1 and 2
IFN- = Treat leukaemia, Kaposi’s 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