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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