Transcript slides#15 Tumor immunology

Tumour Immunology:
What happens when Good Cells go Bad.
Host Defense Against Tumor
Tumor Immunity
• Definition
coordinated biologic process
designed to recognize tumor
cells and their products and to
kill or damage the offending
cells.
Causative agents
Spontaneous
UV and ionizing
radiation
Chemical
carcinogens
Tumour
induction
Genetic
abnormalities (XP)
Virus-induced
(HepC, EBV, HPV)
Immunosuppression
Host Defense Against Tumor
Tumor Immunity
• Tumor Specific Antigens (TSA)
Present only on tumor cells and
not on any normal cells and can be
recognized by cytotoxic T-lymphocytes.
• Tumor Associated Antigens
(TAA)
Not unique to tumors and are
also see on normal cells.
Tumor Antigens
• Tumor Specific Antigens (TSA)
 Cancer testis antigen
 Viral antigen
 Mucin
 Oncofetal antigens
 Antigens resulting from mutational in protein
 B catenin, RAS, P53,CDK4
Tumor Antigens
• Tissue Associated Antigen=TAA
Present in normal cells & tumor cells
e.g. MART-1, gp100, tyrosinase expressed in
melanomas & normal melanocytes
T-cells directed against melanomas will also
destroy normal melanin containing cells
Tumor Antigens
Tumor Associated Antigens(TAA)
• MART-1, gp100, tyrosinase
• Over expressed antigens
• Differentiation- specific antigens
Tumor Associated Antigens(TAA)
• Over expressed Antigens
e.g HER-2
(neu) in 30 % Breast
cancer
( present in normal breast & ovary)
Tumor Associated Antigens(TAA)
• Differentiation- Specific
Antigens
e.g CD10& PSA
Expressed in normal B cells &
Prostate
Used as a marker for tumors
arise from these cells
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
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)
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
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.
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.
Antigens involved in tumour recognition
Tumour-specific antigens
Testes-specific antigens
•Bcr-abl
•CDK-4 / β-catenin
•MAGE 1-3
•NY-ESO-1
(CML)
(melanoma)
(melanoma)
(melanoma)
Differentiation antigens
Tumour associated antigens
•Tyrosinase (TRP-1/2)
•Melan-A
(melanoma)
•Monoclonal Ab (myeloma)
•MUC-1
•α-fetoprotein
•Her-2/neu
•WT-1
•myeloblastin
•Survivin
(myeloma etc)
(many)
(breast)
(many)
(leukaemias)
(many)
How does the adaptive IR target tumours?
Tumour cell present
Ab / ADCC /
cytokine attack
B
Th
Th cells educate
other T/B cells
CTL
Broken up to
release antigens
APC recruits T cells
able to recognise
tumour antigens
T
APC
T
CTL
CTL recognise
and destroy other
tumour cells
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
Direct CTL / NK attack
CTL
Perforin
Granzyme B
FasL
TCR
Fas (CD95)
Class I + Ag
TUMOUR CELL
IR-Mediated Tumour Elimination
NKT
γδ T
NK
NKT
NK
NKT
NK
γδ T
CTL
NK
CD4
CTL
CTL
NK
CD4
CTL
CXC10-12
IFNγ
DC
Innate IR
recognises
tumour cell
establishment
IFNγ
DC
LN
NK cells and other
effectors recruited to
site by chemokines,
which also target
tumour growth directly.
IFNγ
CXC10-12
MΦ
MΦ
MΦ
Tumour-specific T cells
home to tumour site, along
with macrophages and
other effectors to eliminate
tumour cells.
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
Three Es of Immunoediting
Elimination
Equilibrium
Escape
NKT
CD4
NK
CTL
CTL
NK
CTL
NK
CD4
Genetic instability / tumour heterogeneity
CTL
Evasion Mechanisms
How does MM evade the immune response?
myeloma cancer cell
MM cell release
factors which
‘turn off’ T cells
APC recruits CTL
specific for myeloma Ag
T
T
T
Broken up to
release antigens
T
APC
T
T cells recognise
and destroy other
cancer cells
Anti-cancer Therapies and the IR
Category
Example
Effect
IR
Radiation
γ/α
BM ablation/
localised
X
Alkylating
Cyclophosphamide
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
+/-
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.