Download Tumour Immunology fi..

Ali AlQahtani
Fahad Sulaiteen
Mahmoud Qabha
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Objectives
I. Definition of cancer, carcinogenesis
II. Tumor antigens
III. Cancer Immunosurveillance
IV. Army of the host to fight cancers
V. Mechanisms of cancer escape from the
Immune Surveillance
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I. Definitions of Cancer and Carcinogenesis
 Cancers consist of single clones or several
clones of cells that are capable of partially
(benign tumor) or fully (malignant cancer)
independent growth in the host.
 Cancer cells arise from host cells via neoplastic
transformation or carcinogenesis.
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 The essence of carcinogenesis is the activation
(deregulation) of genes that regulate cell growth via
bypassing the host’s regulatory circuits.
 Multiple genes must be deregulated for the
development of fully malignant tumors
 Physical, chemical and biological agents may cause
cancer.
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Classification of cancer
 Carcinomas: epithelial origin involving the skin,
mucous membranes, epithelial cells in glands
 Sarcomas: cancer of connective tissue.
 Lymphomas: T- B-cell, Hodgkin’s, Burkitt’s lymphomas;
- solid tumors
 Leukemia's: disseminated tumors - may be lymphoid,
myeloid, acute and chronic.
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Carcinogens
 Radiation: Ultraviolet light, sunshine; X-rays,
radioactive elements induce DNA damage and
chromosome brakes.
 Chemical: smoke and tar, countless chemicals that
damage DNA (mutagens)
 Oncogenic viruses: insert DNA or cDNA copies of
viral (v) oncogens into the genome of host target cells.
 Hereditary: certain oncogenes are inheritable.
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Oncogenic Viruses
Oncogenic DNA Viruses
Oncogenic RNA viruses
Adenoviridae
Herpesviridae
Poxviridae
Papovaviridae
Hepadnaviridae
Retroviridae
Viral RNA is transcribed to
DNA which can integrate into
host DNA
HTLV 1
HTLV 2
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Oncogenesis
carcinogen
results in mutation
proto-oncogenes
increased GF
increased GF receptors
oncogenes
exaggerated response to GF
tumor
suppressor
genes
inherited
defect
dysfunctional
tumor suppressor
genes
loss of ability to
repair damaged
cells or induce
apoptosis
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Four mechanisms of
oncogene activity to
deregulate cell
division
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Tumor antigens
 Tumorigenesis may lead to expression of new antigens or
alteration in existing antigens that are found on normal
cells. These antigens may include membrane receptors,
regulators of cell cycle and apoptosis, or molecules involved
in signal transduction pathways.
o There are 2 main types of tumor antigens.
1. Tumor-specific transplantation antigens (TSTA);
which are unique to tumor cells and not expressed on
normal cells. They are responsible for rejection of the tumor.
2. Tumor associated transplantation antigens (TATA);
that are expressed by tumor cells and normal cells.
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 Tumor associated transplantation antigens (TATA)
 The majority of tumor Ags are the tumor associated transplantation
antigens (TATA). They may be expressed at higher levels on tumor
cells when compared to normal cells. Alternatively, they may be
expressed only during development of cells and lost during adult life
but re-expressed in tumors. These include the tumor-associated
developmental Ags (TADA) and tumor-associated viral Ags
(TAVA).
 Tumor-associated developmental Ags (TADA) or Onco-fetal
antigens
 These include alpha-fetoprotein (AFP) and carcino-embryonic
antigen (CEA) found secreted in the serum. AFP is found in patients
with hepatocellular carcinoma whereas CEA is found in colon cancer.
These are important in diagnosis.
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Tumor Associated Antigens

Human Chorionic Gonadotropin (HCG)

Alpha Fetoprotein (AFP)

Prostate Specific Antigen (PSA)

Mucin CA 125 (glycoprotein molecules on
both normal epithelium and carcinomas)

Carcinoembryonic Antigen (CEA)
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Cancer Immunosurveillance
The hypothesis was first proposed by Ehrlich in
1909, and modified by Thomas and Burnet in
1957.
• Immunosurveilance: the immunological
resistance of the host against the development of
cancer.
• Now referred to “cancer immunoediting”
encompassing 3 phases: elimination, equilibrium
and escape.
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All components, specific and nonspecific, humoral and
cellular affect tumor progression and growth
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A. Cytotoxic T cells (CTLs)
CD8+ T cells: attaching to class I MHC peptide complex, they destroy cancer cells
by perforating the membrane with
enzymes or by triggering an apoptotic
pathway.
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Perforins, apoptotic signals
MAC or
B cell
(APC)
MHC 1
T
cytotoxic
effector
cells
Exogenous
antigen
T Cytotoxic
Cell Activity
in Tumor
Surveillance
T
cytotoxic
cell
T
cytotoxic
memory
cells
Cancer
Cell
T
cytotoxic
cell
Endogenous
antigen
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B. Helper T cells
CD4+ T cells: reacting to class II MHCpeptide
complex, they secret cytokines.
cytotoxic T cell response (Th1 helper T cells)
antibody response (Th2 helper T cells)
Logistics force
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C. Dendritic Cells
The professional antigen-presenting cells In the
final common pathway for activating naïve T
cells.
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Tumor cell
or tumor
derived
antigen
MAC
MAC
MHC II
IL-1
T
helper
Memor
y cell
T
helper
effector
cell
Interferon
T
helper
cell
Dendritic and Macrophage
Presentation of Tumor
Antigen to CD4 Cells
IL-2
Macrophages and dendritic cells
can directly attack tumor cells,
or more commonly can express
exogenous antigens (TSA’s or
bits of killed tumor cells) to
CD4 cells
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D. NATURAL KILLER CELL
after activation, directly killing tumor cell
Do not recognize tumor cell via antigen specific
cell surface receptor, but rather through receptors
that recognize loss of expression of MHC I
molecules, therefore detect “missing self” common
in cancer.
NK
Perforin and
enzymes
killer activating
receptor
Target cell
(infected or
cancerous)
Tumor surveillance
by NK Cells
Tumor cells produce reactive
oxygen species and stress induced
ligands that can be recognized by
NK cells
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E. Cytokines
• Regulating the innate immune system: NK cells,
macrophages, and neutrophils;
and the adaptive immune system: T and B cells
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• IFN-α -- up regulating MHC class I, tumor antigens, and
adhesion molecules; promoting activity of B and T cells,
macrophages, and dendritic cells.
• IL-2 -- T cell growth factor that binds to a specific tripartite
receptor on T cells.
• IL-12 -- promoting NK and T cell activity, and a growth factor
for B cells
• GM-CSF (Granulocyte-monocyte colony stimulating factor)
-- reconstituting antigen-presenting cells.
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F. Antibody - produced by B cells
• Direct attack: blocking growth factor receptors, arresting
proliferation of tumor cells, or inducing apoptosis.
-is not usually sufficient to completely protect the body.
• Indirect attack: -- major protective efforts
ADCC & CDC
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(1) ADCC (antibody-dependent cell mediated
cytotoxicity )
recruiting cells that have cytotoxicity, such as monocytes
and macrophages.
(2) CDC (complement dependent cytotoxicity)
binding to receptor, initiating the complement system,
“complement cascade”, resulting in a membrane attack
complex, causing cell lysis and death.
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MAC OR NK
TARGET CELL
Antibody-dependent cell-mediated cytotoxicity (ADCC)
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Perforins, apoptotic signals
Tumor
antigen or
tumor cell
MAC
APC
MHC I
T
cytotoxic
cell
T
cytotoxic
effector
cells
MHC II
IL-1
Interferon
T
helper
Memor
y cell
T
helper
cell 1
T
helper
Effector
cell
IL-2
Generally
ineffective
tumor
surveillance,
but some
ADCC
B Cell
Perforins, apoptotic signals
Cancer
Cell
T
helper
2 cell
IL-4
T
cytotoxi
c
memory
cells
T
cytotoxic
cell
Endogenous
antigen
IL-5
Eosinophil
SUMMARY
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1. Altering Their Characteristics :
Loss/downregulation of MHC class I
Down-regulation, mutation, or loss of tumor antigens
Loss of costimulation
2. Suppressing the Immune Response :
ineffective signals to CTL
Alteration in cell death receptor signaling
Immunosuppressive cytokine
3. Outpacing the Immune Response: Tumour cells
can simply proliferate so quickly that the immune
response is not fast enough to keep their growth
in check
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Immunoediting of cancer cells
Elimination refers to
effective immune
surveillance for clones
that express TSA
Equilibrium
refers to the
selection for
resistant
clones (red)
Escape refers to the
rapid proliferation of
resistant clones in the
immunocompetent
host
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Avoidance of tumor surveillance through
release of immune suppressants
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1) Tumor cell production of immune suppressants such as
TGF-,
2) T regulatory cell stimulation with production of
immune suppressants such as TGF- 
Mapara Journal of Clinical Oncology. 22(6):1136-51, 2004
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Tumor cells induce apoptosis in T
lymphocytes via FAS activation
1) Cancer cells express FAS
ligand
2) Bind to FAS receptor on T
lymphocytes leading to
apoptosis
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TUMOR ESCAPE MECHANISMS
Or T regulatory cells
Or kill them
T regulatory cells
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How cancer cells avoid immunosurveillance?
1. Weapons from tumors
2. Defects of immune system
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1. Weapons from tumors
2. Defects of immune system
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(1) Loss/down-regulation of HLA class I (MHC I)
• Total loss: β2 microglobulin mutation, alteration in
antigen processing machinery
• Haplotype loss: LOH in chromosome 6
• HLA allelic loss: mutations of HLA class I genes
• HLA-A, B, C locus down-regulation: alteration of
transcriptional factors
• Compound phenotype: 2 or more independent
mechanisms
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(2) Down-regulation, mutation or loss of tumor
antigens
Tumor antigens (TA)
Tumor associated antigen (TAA)
• Complete loss
• Down-modulation
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(3) Loss of costimulation
Costimulatory molecules B7 1(recognized:
B7.1(CD80)
B7 family
B7.2(CD86)
CD40 L
CD27, CD30
4-1BB
OX40
ICAM-1
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(4) Alterations in cell death
receptor signaling
• Defects in Fas/FasL signaling system:
resistance to apoptosis
• Apoptosis resistance: overexpression
of Bcl-2
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(5) Immunosuppressive cytokines
• a number of immunosuppressive cytokines.
• IL-10 inhibits antigen presentation and IL-12
production.
• TGF-beta induces overproduction of IL-10.
• VEGF (vascular endothelial growth factor),
avoid immune recognition, inhibit the
effector function, prevent T cell activation,
cytokine production.
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(6) Induction of Immunosuppressive cells
• CD4+CD25+ T cells (constitute 5-10% of CD4+ T cells):
immunological tolerance to self-antigens, inhibition of
T cell proliferation.
• Gr1+CD11b+ myeloid cells:
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-- Expressing the granulocyte-monocyte markers
Gr1+CD11b+, accumulate in spleens, lymph nodes and
blood of tumorbearing mice.
-- Inhibiting antibody production, CTL generation, T
cell function, lymphocytic proliferation, CD3 ζ chain
expression.
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(7) Production of other suppressive factors
• IDO (Indoleamine 2, 3-dioxygenase):
expressed in most human tumour tissues
and splenic DC subsets, leading to
blockage of proliferation of T cells
• ganglioside (sialic acid containing
glycosphingolipids)
• Prostaglandins
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Summary: Main defences of the
tumors against immunity
1) Alteration of MHC class I and tumor antigen
expression
2) Dysregulated expression of adhesion / costimulatory
molecules by tumor and/or antigen-presenting cells
3) Changes in T-cell signal transduction molecules, i.e.
cell death ,receptor signaling
4) Induction of immune suppressive cytokines
5) Induction of immunosuppressive cells
6) Secretion of suppressive factors
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1. Weapons from tumors
2. Defects of immune system
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 Immune defects in T cells
 Malfunction of dendritic cell system
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Immune defects in T cells in cancer
• Alterations in the expression of signal transduction
molecules in immune cells.
• Loss of CD 3ζ chain. TCR-CD3 complex. It functions
as a single transducer upon antigen binding.
• Receptor-mediated apoptosis of T cells contributes to
T cell dysfunction.
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Malfunction of dendritic cell system
– Tumor-mediated inhibition of DC generation,
differentiation and maturation
– Functional impairment of DCs: lack of expression of
costimulatory molecules
– Induction of DC apoptosis by tumors
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How do tumors progress?
The fortune of tumor cells
depends on the battle between
immune system and tumor cells
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Turning on the immune response to tumor
cells through administration of immune
stimulants
(A) Tumor cells can avoid activating innate responses by producing inhibitory cytokines
and down-regulating or secreting ligands for activating receptors. M , macrophage;
TCR, T cell receptor.
(B) (B) Activation of innate responses can be enhanced by administering adjuvants,
ligands for costimulatory proteins, cytokines, or drugs that directly trigger innate
immune cells. GalCer, -galactosylceramide.
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This is the End,,,
Hold your Breath and count to Ten
Ali Alqahtani
Fahad Sulaiteen
Mahmoud Qabha
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