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TUMOR IMMUNOLOGY
Cancer is a result of multiple mutations
• MORE THAN 100 VARIOUS TUMOR TYPES
• MULTISTEP TUMORIGENESIS
• DYNAMIC CHANGE OF TUMOR GENOME
– Genetic instability
– Oncogenes – ‘gain of function’ change
– Tumor suppressor genes – recessive ‘loss of function’ change
• PROGRESSIVE TRANSFORMATION
– Benign tumor abnormal, but limited growth
– Malignant tumor unlimited growth, break basal membranes,
invasion
– Metastatic tumor seeds new tumors at distant sites.
• MULTIPLE LIMITING AND INHIBITORY CHECK POINTS
– Growth advantage
– Selection
• REGULATORY CIRCUITS
– Inherent cell autonomous regulatory mechanisms
– Microenvironmental factors
INDEPENDENT OF THE IMMUNE SYSTEM
Benign or malignant tumors
Malignant transformation
ACTIVATION OF ONCOGENES
Mitogens
Growth factor receptors
Secondary messengers
Tarnscriptional activators
Cell cycle genes
Malignant cell
INACTIVATION OF TUMOR
SUPPRESSOR GENES
Tissue cell
Growth inhibitors
Transcriptional repressors
Cell cycle inhibitors
Programmed cell death genes
DNA repair enzymes
Tumor stem
cell
ACQUIRED PROPERTIES
Independent growth factor signals
Resistance to growth inhibitory factors
Avoid apoptosis
Unlimited proliferation
Sustained angiogenesis
Tissue migration and metastasis
Hanahan D és Weinberg RA 2000 Cell
The „multi-hit” model of tumorigenesis
Reaction of the immune system
Normal epithelial cells
2 APC mutation
Inherited
TOLERANCE
Adenomatous
polip
1 Ras mutation
Adenomatous
polip
2 p53 mutation
Colon carcinoma
Chromosomal
translocation
Individual
TSA
RECOGNITION
Tumor antigens
Common
TAA
CEA
DANGER
Metastatic colon
carcinoma
IMMUNE
RESPONSE
Knudson A.G. 2001
INNATE/AQUIRED
IMMUNITY
TOLERANCE
Oncogenesis
Mechanism
Growth
promotion
Loss of
tumor
suppressor
gene
function
Limitation
of
Apoptosis
Action
Example
Overexpression of growth factor receptors (such as epidermal growth factor, or EGF) making
cells more sensitive to growth stimuli
c-erb-B2
Increased growth factor signal transduction by an oncogene that lacks the GTPase activity
that limits GTP induction of cytoplasmic kinases that drive cell growth
ras
Overexpression of a gene product by stimulation from an oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocation of a gene where it is controlled by
surrounding genes to a place where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA transcriptional activation to promote
entry into the cell cycle
c-myc
Lack of regulation of cell adhesion with loss of growth control through cell interaction
APC
Loss of down-regulation of growth promoting signal transduction
NF-1
Loss of regulation of cell cycle activation through sequestation of transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of inhibition of cell proliferation that
allows DNA repair
p53
Overexpression of gene, activated by translocation, prevents apoptosis
bcl-2
VARIOUS ONCOGENES ARE ASSOCIATED WITH DEFINED
NEOPLASMS
Oncogene
Associated Neoplasms
c-erb-B2
Breast and ovarian carcinomas
ras
Many carcinomas and leukemias
c-sis
Gliomas
c-abl
Chronic myelogenous leukemia, acute lymphocytic
leukemia
c-myc
Lymphomas
BRCA-1
Breast and ovarian carcinomas
APC
Colonic adenocarcinomas
NF-1
Neurofibromas and neurofibrosarcomas
Rb
Retinoblastomas, osteosarcomas, small cell lung
carcinomas
p53
Many carcinomas
bcl-2
Chronic lymphocytic leukemia, lymphomas
LARYNGEAL EPITHELIUM
squamous
CERVICAL
dysplastic squamous
normal
normal squamous
The first step toward neoplasia is cellular
transformation. Here, there is metaplasia of
normal respiratory laryngeal epithelium on the
right to squamous epithelium on the left in
response to chronic irritation of smoking.
This is the next step toward neoplasia. Normal
cervical squamous epithelium at the left, but
dysplastic squamous epithelium at the right.
Dysplasia is a disorderly growth of epithelium, but
still confined to the epithelium. Dysplasia is still
reversible.
The two forms of cellular transformation that are potentially reversible, but may
be steps toward a neoplasm, are:
Metaplasia: the exchange of normal epithelium for another type of epithelium.
Metaplasia is reversible when the stimulus is taken away.
Dysplasia: a disordered growth and maturation of an epithelium, which is still
reversible if the factors driving it are eliminated.
CHROMOSOMAL TRANSLOCATION IN BURKITT’S
LYMPHOMA
8
c-myc
14
8q-
14q+
CH
VH
Uncontrolled proliferation due to the activation of c-myc
oncogene
EBV induced tumor
CH
VH
c-myc
THE IMMUNE RESPONSE TO TUMORS
Hidden, changing, proliferating, evolving target
• Immune surveillence
– Few non-self antigens
– Poorly immunogenic
– Recognized by B and T
lymphocytes
• Tolerance induction
– Tumor antigens do exist
– Recognized primarily by T
lymphocytes
– Induce tolerance
TUMOR ANTIGENS
Tumor associated antigens – TA
Present also in normal cells
Aberrant/disregulated expression in tumor cells
Tumor specific antigens – TSA
Unique for individual tumors or tumor types
IMMUNE SYSTEM
Tumor-specific immune responses can be induced
Cytotoxic T lymphocytes can eradicate tumors
MHC-dependent rejection of tumors
Infective facial tumor in the inbread populations of
the Tasmanian devil
Tumor antigens and tumor associated antigens
Tumor-specific antigens
Cancer/testis
antigens
are
expressed almost entirely by
cancerous cells, showing little or no
expression in healthy tissue, with
the exception of normal testis,
embryonic ovaries and placenta.
No MHC expression
Many of them X-linked
Over 100 in total --- Potential
targets for immune therapy
STRUCTURE AND SOURCE OF TUMOR ANTIGENS
•
MUTATED ONCOGENS AND TUMOR SUPPRESSOR GENES
– Involved in transformation
– Cytosolic novel determinants - no major targets
– Cellular proto-oncogenes  oncogene Ras, p53, Abl
• Point mutation, deletion, chromosomal translocation, viral gene insertion
•
•
•
OTHER MUTATED GENES – not required for transformation
– Peptides derived from diverse random mutants of host cellular proteins
ABERRANTLY OVEREXPRESSED NORMAL CELLULAR PROTEINS
– Low/rare expression in normal cell – ignorance by the immune system
TUMOR ANTIGENS ENCODED BY GENOMES OF ONCOGENIC VIRUSES
– Immunogenic shared viral proteins
• DNA viruses – Papova, Herpes, Papilloma
• RNA viruses – Retroviruses HTLV
•
•
ONCOFETAL ANTIGENS
– Silenced during development  de-repressed in tumor cells
– Tumor markers – carcinoembryonic antigen CEA, specific for carcinomas
– Alpha-fetoprotein AFP, hepatocellular carcinoma
ALTERED GLYCOLIPIDS
– Ganglioside, blood group related antigens, mucin
•
TISSUE-SPECIFIC DIFFERENTIATION ANTIGENS
– CD10/CALLA Common Acute Lymphoid Leukemia Antigen, Melanoma
ELIMINATION
EQUILIBRIUM
ESCAPE
Immunsurveillence
NK/γδ
macrophage
NK/γδ
DS
CD4/CD8
METASTASIS
macrophage
Genetic instability
Immune selection
CD4/CD8
DS
CD8
TUMOR
ESCAPING TUMOR
VARIANTS
PROTECTION
Treg cells
CD8
Activation of tumor-specific T-cells by DC
Cross-presentation
INDUCTION OF A PROTECTIVE ANTI-TUMOR IMMUNE RESPONSE
REQUIRES THE COLLABORATION OF DENDRITIC CELLS AND TLYMPHOCYTES
TNF
IFN
APOPTOTIC
TUMOR CELL
CD40
CD40L
CD40
PS
CD4+
TH1
CD40L
IL-2
HSP
Carbohydrate
APC
DC
MHCII
IL-12
IL
- 12
Oxidation
ICAM-3
M
H
CI
TUMOR
CROSS PRIMING
IFN
Tumor Ag
CD8+
Tc
B
CONSEQUENCES OF T-CELL MEDIATED IMMUNITY
Cytotoxic T-lymphocytes
recognize tumor cells
Activated cytotoxic T-lymphocytes
kill tumor cells
TOLERANCE INDUCTION BY DENDRITIC CELLS
M1 macrophage: MHCII, CD80, 86
High iNOS,
Tumor-associated
macrophage (upto 40% of
non-malignant cells)
M
IL-10
CD40L CD4+
M2 macrphage: arginase +
CD4+
CD25+
IDC
DC2
SIGNAL 1
SIGNAL 2
SIGNAL 3
Tumor antigen
Tumor cell
Activated APC
Natural immunity
Inflammation
YES
NO
YES
NO
NO
CD4+
reg
CD8+
Tc
•
ESCAPE MECHANISMS OF TUMOR CELLS AND TUMOR
TISSUES
TUMOR ANTIGENS
–
–
–
–
–
•
Soluble tumor antigens – inhibit recognition on the cell surface
Antigen modulation – antibody dependent internalization
Masking – antibody binds, no effector function
Low immunogenicity
Peptide antigens – mutations affecting Tc or Th epitopes
ANTIGEN PRESENTATION
– Direct presentation – non professional APC, no MHC class II, no co-stimulatory
molecules
– Indirect presentation – by professional APC, soluble CD40 and CD40 ligand inhibit
•
CYTOTOXIC T CELL ACTIVITY
– MHC – mutation, altered intracellular transport, β2m, locus, allele
– Peptide loading – mutation, tumor derived peptides are not presented, TAP
•
APOPTOSIS
– Soluble Fas – inhibits Fas ligand-mediated apoptosis
•
TUMOR DERIVED INHIBITORY FACTORS
– TGFβ – G1 block, inhibits tumor growth if sensitive tumors loose their TGFβ
receptor
– TGFβ inhibits immune cell activation
– PGE2 – immune suppression
•
TUMOR DERIVED POTENTIATING FACTORS
– Angiogenesis factors – secreted by tumor tissue cells or by immune cells
Human epithelial tumours can inhibit the response
of lymphocytes expressing NKG2D
AZ AKTÍV TUMOR-SPECIFIKUS
IMMUNTERÁPIA LEHETŐSÉGEI
ANTI-TUMOR IMMUNOTHERAPY
A tumor antigének beviteli módja
Tumor proteinderived peptide
Anti-idiotipe Ab
Tumor protein
Vírus-tumor genome
Modified tumor cell
Plasmid DNA
Modified DC
Irradiated tumor cell
Tumor cell lysate
Heat shock
protein
Loaded DC
Mocellin S et al.
Lancet Oncology 2004
DIAGNOSIS OF TUMORS BY PET
Vaccination of melanoma patients may cause
their tumor to regress