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

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Tumour immunology what happens when good cells go bad l.jpg

Tumour Immunology:What happens when Good Cells go Bad.

Dr Alasdair Fraser

Sylvia Aitken Research Fellow Section of Experimental Haematology, Glasgow Royal Infirmary


Prevalence of cancer in uk l.jpg

Prevalence of cancer in UK


Us mortality 2002 l.jpg

US Mortality, 2002

No. deaths

% of all deaths

Rank

Cause of Death

1.Heart Diseases696,947 28.5

2.Cancer557,271 22.8

3.Cerebrovascular diseases162,672 6.7

4.Chronic lower respiratory diseases124,816 5.1

5.Accidents (Unintentional injuries)106,742 4.4

6.Diabetes mellitus73,249 3.0

7.Influenza and pneumonia65,681 2.7

8.Alzheimer disease58,866 2.4

9.Nephritis40,974 1.7

10.Septicemia33,865 1.4

Source: US Mortality Public Use Data Tape 2002, National Center for Health Statistics, CDCP, 2004.


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Men710,040

Women662,870

2005 Estimated US Cancer Cases

32%Breast

12%Lung / bronchus

11%Colon / rectum

6%Uterine corpus

4%Non-Hodgkin’s

4%Melanoma of skin

3% Ovary

3%Thyroid

2%Urinary bladder

2%Pancreas

21%All Other Sites

Prostate33%

Lung / bronchus13%

Colon / rectum10%

Urinary / bladder7%

Melanoma of skin5%

Non-Hodgkin’s4%

Kidney3%

Leukemia3%

Oral Cavity3%

Pancreas2%

All Other Sites17%

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.

Source: American Cancer Society, 2005.


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Men295,280

Women275,000

2005 Estimated US Cancer Deaths

27%Lung and bronchus

15%Breast

10%Colon and rectum

6%Ovary

6%Pancreas

4%Leukemia

3%Non-Hodgkin’s

3%Uterine corpus

2%Multiple myeloma

2%Brain / ONS

22% All other sites

Lung / bronchus31%

Prostate10%

Colon / rectum10%

Pancreas5%

Leukemias4%

Esophagus4%

Liver / bile duct3%

Non-Hodgkin’s 3%

Urinary / bladder3%

Kidney3%

All other sites 24%

ONS=Other nervous system.

Source: American Cancer Society, 2005.


Relative survival during three time periods l.jpg

Site

1974-1976

1983-1985

1995-2000

Relative Survival (%) during Three Time Periods

All sites505364

Breast (female)757888

Colon 505863

Leukemia344146

Lung and bronchus131415

Melanoma of the skin808591

Non-Hodgkin lymphoma475459

Ovary3741 44

Pancreas334

Prostate677599

Rectum495564

Urinary bladder737882

*5-year relative survival rates based on follow up of patients through 2001.

Source: SEER Program (1975-2001), NCI 2004.


Causative agents l.jpg

Spontaneous

UV and ionizing radiation

Chemical carcinogens

Tumour induction

Genetic abnormalities (XP)

Virus-induced (HepC, EBV, HPV)

Immunosuppression

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 animals…genetic changes must be common and a proportion…will 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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......................................................

IFNγ and lymphocytes prevent

primary tumour development

and shape tumour immunogenicity

Vijay Shankaran*, Hiroaki Ikeda*, Allen T. Bruce*, J. Michael White*,

Paul E. Swanson*, Lloyd J. Old² & Robert D. Schreiber*

.............................................................................................................................................

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 γ/δ 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+/CD8α+ 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 / β-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)

  • α-fetoprotein (many)

  • Her-2/neu (breast)

  • WT-1 (many)

  • myeloblastin (leukaemias)

  • Survivin (many)


How does the adaptive ir target tumours l.jpg

Tumour cell present

CTL

CTL

APC

Broken up to release antigens

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 (TNFα, IFNs etc) and antiangiogenic factors


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CTL

Direct CTL / NK attack

FasL

Perforin Granzyme B

TCR

Fas (CD95)

Class I + Ag

TUMOUR CELL


Ir mediated tumour elimination l.jpg

NKT

NKT

NKT

NK

CTL

γδ T

γδ T

NK

NK

NK

CD4

CTL

NK

CTL

CD4

CTL

CXC10-12

IFNγ

IFNγ

LN

CXC10-12

IFNγ

NK cells and other effectors recruited to site by chemokines, which also target tumour growth directly.

Tumour-specific T cells home to tumour site, along with macrophages and other effectors to eliminate tumour cells.

DC

DC

Innate IR recognises tumour cell establishment

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


How does mm evade the immune response l.jpg

myeloma cancer cell

MM cell release factors which ‘turn off’ T cells

T

APC recruits CTL specific for myeloma Ag

APC

T cells recognise and destroy other cancer cells

Broken up to release antigens

T

T

T

T

How does MM evade the immune response?


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Anti-cancer Therapies and the IR


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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.


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