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Immunbiology of Tumors
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Tumor cells are considered as “parasites” of the
body
They are formed also in healthy subjects but antitumor control mechanism eliminate them
Tumor cells escape control with
- fast proliferation
- mutations
- high diversity (“mini evolution”)
Inducers of malignant transformation of cells
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chemical carcinogens e.g. tar
physical carcinogens e.g. UV or X-ray
viral - both DNA or RNA viruses
Oncogens
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gene coding a protein which can induce malignant
transformation - viral or v-onc (they are only exons)
proto-oncogens - are present and function in
physiologically intact cells - cellular or c-onc (they
are exons or introns)
these genes are well-conserved structures
their main function is: to modulate proliferation or
apoptosis
Neoplastic transformation
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genetic alterations
environmental factors
expression of new, non-self cell surface
antigens
the non-self antigens are detected by the
immune system
Potential sources of tumor antigens
Category
Example
Oncogene product
muation in RAS codon 12 (pancr. cc.)
bcr/abl protein (chr. myeloid leukemia)
Embryonic proteins
MAGE family (melanoma, breast cc.)
Viral proteins
Epstein-Barr virus (Hodgkin’s lymph.)
Hepatitis B (hepaticellular cc.)
Tissue spec. antigen
Tyrosinase (melanoma)
Mutant tu. suppressor prot.
p53 (several cc.)
Idiotypic epitopes
T-cell receptor idiotypes (T-cell lymph.)
Formation of Tumor Specific Antigens
effect of mutagen
mRNA
protein
MHC
changed peptide
Tumor antigens
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Tumor specific antigens (TSA)
expressed by tumor cells only
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Tumor associated antigens (TAA)
expressed by tumor cells and
some normal cells, too
Characterization of TSA (1)
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expression of TSA is induced by chemical
carcinogens or X-rays.
somatic mutations result TSA
each carcinogen can induce unique or specific
class of TSA
Characterization of TSA (2)
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T-cell receptors recognize peptides bound to the
antigen - binding to the binding cleft of MHC
molecules
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TSA that evoke cytotoxic T cell response are derived
from peptides uniquely synthesized by tumor cells
and expressed on the surface of MHC I.
Normal cell
Normal cytoplasmic
protein
Peptide fragment
CD8+ T cell
MHC I antigen
CD8+ T cell
CD8+ T cell
Responses elicited by tumor cells
Antigen-specific effects
on the tumor cell
Apoptosis of tumor cells
SURVIVAL
Escape mechanisms
Immunologic tolerance
METASTASIS, DEATH
Antigen-specific effect of Tc cells
MHC I.
Tc
TCRa
TCRb
Tumor cell
CD8
TNFb
FasL
APOPTOSIS
Fas
APOPTOSIS
Mechanisms by which TSAs are derived
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Peptides without structural motives for binding to
MHC molecules of the host
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Mutation in gene encoding converting proteins that
convert the peptide to a form binding to MHC and
displayed az TSA on cell surface
40% melanomas
20% breast ca.
30% lung small cell ca.
MAGE-1
express
MAGE-1
(melanoma antigen-encoding gene)
- embryonal protein,
expression is de-repressed in tumors
- present also in some normal cells e.g. testis
TAA
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Oncofetal antigens
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Differentialtion specific antigens (DSA)
Oncofetal antigens
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normally expressed during a specific phase of
enbryogenesis
they are practically in mature, differentiated tuissues
they are not immunogenic
they do not possess functional role in tumor
immunity
Their significance: they are diagnostic and
prognostic markers
serum cc. correlates with tumor mass, level of
differentiation and response to therapy
Ideal tumor markers
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specific for the type of the tumor
released only in response to tumor
results proportional to tumor mass
quantitatively reflects to tumor response
elevated even with low tumor burden
Carcinoembryonic antigen (CEA)
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discovered in extracts of adenocc. of colon
a group of heterogeneous glycoproteins - M.W. 200
kD
normally present in embryonic and fetal digestive
tissues
detected by RIA or immunoenzymatic technique
elevated (over 5 ng/ml) in gastrointestinal, breast,
pancreas, lung tu. and alcoholic cirrhosis,
inflammations
Alpha-fetoprotein (AFP)
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increased in hepatocellular cc. and malignant
teratomas
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serum levels are increased in metastatic tumors in
liver and acute hepatitis
Prognostic roles of tumor markers
†
Se AFP ng/ml
1000
†
†
100
chemotherapy - no response
chemotherapy - response
surgery with regrowth or metastasis
surgery
In experimental model TSA assessed by:
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ability to resist a live tumor implant following the
immunization with tumor cells
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ability to resist when the model is infused with
sensitized T cells from a syngeneic donor
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in vitro demonstration of tumor cell destruction by
cytotoxic T cells gained from a tumor immunized
animal
Host immune response to tumor
Experimental
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Colony inhibition of tumors by sensitized
lymphocytes
Tumor extracts induce lymphocyte blast
tratnsformation
Lymphocyte-enhanced cytotoxicity
Macrophage-enhanced phagocytosis
Host immune response to tumors
Clinical
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Spontaneous regression
Regression of tu. - sublethal doses of chemotherapy
Regression of metastasis - resection of primary tumor
Mononuclear cell infiltration
High incidence of tu. after clinical immunospureassion
High incidence of tu in immunodeficiency
Increased incidence of tu. in aging
Cellular effectors that mediate immunity (1)
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Cytotoxic T-Ly - protective role against virus- associated
neoplasms (e.g. EBV)
NK-Ly - capable to destroy tumor cells w\o prior
sensitization
Only tu. cells w\o MHC are lysed: NK-Ly recognize
carbohydrate components of the membrane by NKR-P1
rec. BUT Ly49 rec. recognize MHC I. and blocks NK-Ly
activity
(This is the first-line of defense.)
Activation with IL-2: NK Ly lyse a variety of tu.
T Ly
Complementary anti-tumor mechanisms
NK Ly
Cellular effectors that mediate immunity (2)
Macrophages (activated) possess selective cytotoxicity against
tumor cells
T Ly
NK Ly
collaborate in anti-tumor reactivity
Macrophages
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(e.g. INF-g secreted by T and NK Ly activator of macrophages.
Production of reactive oxygen, or secretioon of TNF-a)
 Humoral mechanisms:
activation of complement
induction of ADCC by NK Ly
Cellular effectors of antitumor immunity
IL-2
CTL
NK Ly
Peptide
TC-rec.
NK-rec.
MHC I
Antigen
IgG
Fc-rec.
NK Ly
INF-g
TNF-a
Macrophage
Effector Mechanisms in Tumor Immunity
Humoral:
 opsonisation and phagocytosis
 complement mediated lysis
 loss of cell adhesion (antibody dependent)
Cellular:
 T Ly
 Antibody-dependent cytotoxicity
 NK Ly
 Lymphokine-activated killer (LAK) cells
 Macrophages (also activated by lymphokines)
Immuno Surveillance
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In 5% with congenital immunodeficiencies develop
cancer (200x rate)
In immunsuppressed patients (80x rate)
AIDS, lymphomas, chronic infectious mononucleosis
or malignant lymphomas
Escape of Tumors
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Continuous shedding of tumor antigens - solubile
antigens
Reults:
- impossible to detect selectively these
cells
- only NK-Ly can detect these cells,
BUT they are not present everywhere
Effects of NK on the target cells
Killer inhibitory receptor = KIR; Killer activator receptor = KAR
target
MHC I
KIR
KAR
+ -
KAR
KIR
+
NK-Ly
NO apoptosis
Apoptosis
More Escape Mechanisms from Immuno
Surveillance
• selective outgrowth of antigen negative variants
• loss or reduced expression of HLA antigens
• no costimulation - no sensitization- anergic T Ly apoptosis of T Ly
• expression of local inhibitory molecules (TNF- b or
Fas ligand
• immunosuppression (chemicals, radiation, TGF-b)
Immunologic activation and tolerance
Viral infection
Cancer
Danger signals
(GM-CSF, TNF-a)
Antigen uptake by
activated APC
T cell
T cell
Tumor-specific T cells become
tolerant
Costimulatory signal
(B7, Il-12)
T cell
Virus-specific T cells become
activated
Failure of Immune Response to Tumor
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Some tumors arise in areas not accessible to the
effector cells (e.g. eye, CNS)
Antigenic modulation - antigens of tumor cells may
undergo several changes
Blocking factors - immune complexes or cytophilic
antibodies can mask tumor antigens or prevent
binding by effector cells or lytic antibodies
Prospects for Immunotherapy to generate
antitumor responses (1)
1890 Wiliam Coley: bacterial extracts to activate general immunity
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Tumor cell vaccines - there are T cells directed against the
tumor - their number could be increased with autologous or
allogeneic tumor cells (the replication is prevented by
irradiation)
Immunization with tumor-specific peptides - only for tumors
for which TAA have been cloned and peptides synthesised
Cytokine therapy - increasing the levels of some cytokines (IL2, IFN, GM-CSF, IL-7, IL-12)
Problems: short life-time, toxicity, non-specific cytokines.
Prospects for Immunotherapy to generate
antitumor responses (2)
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Monoclonal antibodies - used to deliver immunotoxins.
radioisotopes, drugs. Bivalent antibodies recognize both T
cells and TAA - they guide T cell to the tumor.
Gene therapy - combines the concepts of “tumor cell
vaccines” and “cytokine therapy” by expressing genes coding
for cytokines, costimulatory molecules or MHC.
Adoptive immunotherapy - with antitumor cells, tumor
infiltrating lymphocytes (TIL) or lymphokine-activated killer
(LAK) cells.
Problems: growing the large number of cells required, loss of
antigene specificity for T cells, altered homing pattern