Tumour Immunology: What happens when Good Cells go Bad.

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Tumour ImmunologyWhat happens when Good Cells
go Bad.
Dr Alasdair Fraser Sylvia Aitken Research Fellow
Section
of Experimental Haematology,
Glasgow Royal Infirmary
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Prevalence of cancer in UK
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US Mortality, 2002
No. deaths
of all deaths
Rank
Cause of Death

• 1. Heart Diseases 696,947 28.5
• 2. Cancer 557,271 22.8
• 3. Cerebrovascular diseases 162,672
  6.7
• 4. Chronic lower respiratory diseases 124,816
  5.1
• 5. Accidents (Unintentional injuries) 106,742
  4.4
• 6. Diabetes mellitus 73,249 3.0
• 7. Influenza and pneumonia 65,681 2.7
• 8. Alzheimer disease 58,866 2.4
• 9. Nephritis 40,974 1.7

Source US Mortality Public Use Data Tape 2002,
National Center for Health Statistics, CDCP, 2004.
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2005 Estimated US Cancer Cases
32 Breast 12 Lung / bronchus 11 Colon /
rectum 6 Uterine corpus 4 Non-Hodgkins 4
Melanoma of skin 3 Ovary
3 Thyroid 2 Urinary bladder 2 Pancreas 21 A
ll Other Sites
Prostate 33 Lung / bronchus 13 Colon /
rectum 10 Urinary / bladder 7 Melanoma of
skin 5 Non-Hodgkins 4 Kidney 3 Leukemia 3
Oral Cavity 3 Pancreas 2 All Other Sites 17
Excludes basal and squamous cell skin cancers
and in situ carcinomas except urinary
bladder. Source American Cancer Society, 2005.
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2005 Estimated US Cancer Deaths
27 Lung and bronchus 15 Breast 10 Colon
and rectum 6 Ovary 6 Pancreas
4 Leukemia 3 Non-Hodgkins 3 Uterine
corpus 2 Multiple myeloma 2 Brain /
ONS 22 All other sites
Lung / bronchus 31 Prostate 10 Colon /
rectum 10 Pancreas 5 Leukemias 4 Esophagus 4 L
iver / bile duct 3 Non-Hodgkins 3 Urinary /
bladder 3 Kidney 3 All other sites
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ONSOther nervous system. Source American Cancer
Society, 2005.
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Relative Survival () during Three Time Periods
     

• All sites 50 53 64
• Breast (female) 75 78 88
• Colon 50 58 63
• Leukemia 34 41 46
• Lung and bronchus 13 14 15
• Melanoma of the skin 80 85 91
• Non-Hodgkin lymphoma 47 54 59
• Ovary 37 41 44
• Pancreas 3 3 4
• Prostate 67 75 99
• Rectum 49 55 64
• Urinary bladder 73 78 82

5-year relative survival rates based on follow
up of patients through 2001. Source SEER
Program (1975-2001), NCI 2004.
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Causative agents
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How do cancer cells differ from normal?

• Clonal in origin
• Deregulated growth and lifespan
• Altered tissue affinity
• Resistance to control via apoptotic signals
• Change in surface phenotype and markers
• Structural and biochemical changes
• Presence of tumour-specific antigens

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Evidence for IR to tumours
Animal models showed that pre-treatment of mice
with killed tumour material could protect against
a subsequent challenge. T cell ablation or
T-cell deficient mice removed this
protection. Transfer of T cells from an
immunized mouse could protect a naïve mouse from
tumour challenge.
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Immune Surveillance of Cancer

• Proposed originally in 1909 by Paul Ehrlich
• Refined in late 1950s by Burnet and Thomas

In animalsgenetic changes must be common and a
proportionwill represent a step towards
malignancy. there should be some mechanism for
eliminating such potentially dangerous mutant
cells and it is postulated that this mechanism is
of immunological character. FM Burnet The
concept of immunological surveillance (1970)
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Immune Surveillance of Cancer

• Subsequent evidence against immune surveillance,
  particularly from nude mice studies.
• More recent studies identify effector populations
  and KO models utilised.

• Definitive evidence of immune surveillance
  published by Schreiber et al in 2001

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Evidence of Immune Surveillance in Humans

• Immunosuppression leads to increased development
  of viral-derived tumours (Kaposi / NHL / HPV).
• Organ transplant increases malignant melanoma
  risk. (0.3 general paediatric
  popn., 4 paediatric transplants)
• 3-fold higher risk of sarcoma.
• High TIL presence correlates with improved
  survival.
• NK or ?/d T cell loss correlates with increased
  tumour pathogenicity.

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Innate control of cancer
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NK cell control of cancer in humans

• NK / NKT cells in animal models destroy tumours
  with down-regulated Class I expression.
• Control of haematological malignancy after
  haplotype-mismatched BM/SC transplant
  Costello et al (2004) Trends Immunol.
• Maintenance of remission in acute leukaemias
  dependent upon CD56/CD8a NK cells
  Lowdell et al (2002) Br.J.Haematol.

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Antigens involved in tumour recognition

• Tumour-specific antigens
• Bcr-abl (CML)
• CDK-4 / ß-catenin (melanoma)

• Testes-specific antigens
• MAGE 1-3 (melanoma)
• NY-ESO-1 (melanoma)

• Differentiation antigens
• Tyrosinase (TRP-1/2)
• Melan-A (melanoma)
• Monoclonal Ab (myeloma)

• Tumour associated antigens
• MUC-1 (myeloma etc)
• a-fetoprotein (many)
• Her-2/neu (breast)
• WT-1 (many)
• myeloblastin (leukaemias)
• Survivin (many)

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How does the adaptive IR target tumours?
Ab / ADCC / cytokine attack
Th
B
Th cells educate other T/B cells
APC recruits T cells able to recognise tumour
antigens
CTL recognise and destroy other tumour cells
T
T
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Effector mechanisms against cancer

• Monocyte / macrophage release lytic enzymes and
  phagocytose necrotic material
• Antibody against tumour antigens
• Induction of tumour-specific CTL and TIL
• Initiation of NK / CTL cytotoxic responses
• Release of cytokines / chemokines (TNFa, IFNs
  etc) and antiangiogenic factors

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Direct CTL / NK attack
FasL
Perforin Granzyme B
TCR
Fas (CD95)
Class I Ag
TUMOUR CELL
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IR-Mediated Tumour Elimination
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Immunoediting- The Great Escape!

• Strong evidence that IR controls and eradicates
  nascent cancer cells
• Immunoediting eventually produces low
  antigenicity tumour cells
• Pressure from immune system coupled with genomic
  instability selects for escape

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Three Es of Immunoediting
Elimination
Equilibrium
Escape
NKT
CD4
CTL
NK
NK
NK
CTL
CTL
CTL
CD4
Genetic instability / tumour heterogeneity
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Evasion Mechanisms
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How does MM evade the immune response?
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Anti-cancer Therapies and the IR
Category Example Effect IR
Radiation ? / a BM ablation/ localised X
Alkylating Cyclo-phosphamide DNA X-linking X
Anti-metabolites 5-FU Ara-C/Ara-A Inhibit DNA synthesis X
Natural products Taxanes Vinca alkaloids Mycins DNA damage or microtubule inhibitors X
Metals Cisplatin arsenicals DNA X-linking and cytotoxicity X

New drugs Imatinib Thalidomide Signalling inhibitor /-
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Summary

• Cancers are one of the leading causes of death
  throughout the world.
• Tumours arise from single events (spontaneous /
  viral / induced) and altered characteristics
  produce unregulated growth.
• Majority of tumours dealt with by IR before
  development progresses to clinical stage.
• Immunoediting leads to development of escape
  clones.
• Established tumours can prevent immune attack in
  the absence of further triggers.