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Tumour immunology and immunotherapy ppt uk

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					Tumour Immunology
        &
 Immunotherapy


 Dr Usama ALAlami

                    1
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
                                                            4
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                                      5
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


                                                                6
    Growth Factor Receptors

Proto-oncogenes      Growth Factor
                       Receptor
      fms            CSF-1 receptor

     erbB                 EGFR

     neu          Protein related to EGF
                         receptor
     erbA           Thyroid hormone
                         receptor       7
[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


                                                             8
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

                                                        9
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
                                                           10
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




                                                        11
Tumours Of The Immune System



Tumours of the immune system


  Leukaemias     Lymphomas


                               12
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

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
                                                             13
                 Tumour Antigens



                       Tumour Antigens


Tumour-associate antigens (TAA) Tumour-specific antigens (TSA)

                                                             14
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



                                                          15
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)
                                                           16
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)




                                                            17
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




                                                    18
[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

                                                        19
[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




                                                      20
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


                                                           21
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




                                                             22
     Cancer Immunotherapy

1)     Immune Adjuvants


                        Bacterial ajuvants


                      Activate macrophages


               Increase interleukin-1 (IL-1) secretion


            Increase helper T lymphocyte (Th) activation


                  Increase cell-mediated immunity
                                                           23
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




                                                            24
Reading

Janis Kuby (1994). Immunology. 2nd edition. W.H.Freeman an
Company. Chapter 25




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