Title: Immunological aspect of tumor
1Immunological aspect of tumor
- Ahmad Shihada Silmi
- Hematologist Immunologist
- IUG
2Definition
- A tumor erupts as a result of a mutation or
damage to one cell leading to abnormal
proliferation.
3Once a tumor cell has erupted it can be one of
the three kinds
- Not viable the control mechanism of the cell it
self discover the mutation induce apoptosis. - Immunogenic the mutation is expressed on the
cell surface in such a way that the immune
defense system recognize it as non-self and
induce apoptosis. - Not recognizable the mutation is expressed on
the cell surface so diffusely that the immune
defense system recognize as self, thus giving it
the opportunity to proliferate.
4Four mechanisms of oncogene activity to
deregulate cell division
5A closer look at p53
6Oncogenesis
carcinogen results in mutation
increased GF
increased GF receptors
proto-oncogenes
oncogenes
exaggerated response to GF
tumor suppressor genes
loss of ability to repair damaged cells or
induce apoptosis
dysfunctional tumor suppressor genes
inherited defect
7Cancer cells are different
- Escape normal intercellular communication
- Allow for rapid growth
- Increased mobility of cells
- Invade tissues
- Metastasis
- Evade the immune system
8Tumors and the Immune System
- Clinical tumors, by definition, have been able to
evade the immune response - Deletional Tolerance
- Nondeletional Tolerance
9QUESTIONS FOR TUMOR IMMUNOLOGY
- What does the immune system target on cancer
cells? - What is the antitumor response?
- Why is it ineffective?
- How can we augment it?
10EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND
IMMUNE RESPONSE
11Tumor Antigens
- a. Tumor specific antigens (TSA)-present on t.c.
, not on normal cells. - b. Tumor associated antigens (TAA)-present on
t.c. some normal cells
12Tumor Specific Antigens
- Mutated tumor cell proteins
- Tumor-specific mutated oncogenes or tumor
suppressor genes - Over-expression of normal antigens
- Viral oncogene expression on surface of the cell
13TUMOR OVEREXPRESSION OF NORMAL AG
14Tumor 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)
15CEA TUMOR ANTIGEN IN COLON CANCER
1000
100
CEA (ng/ml)
10
Normal Range
0
200
300
400
100
Surgical Removal of Tumor
Clinical Manifestations Appear
Time in Days ?
16Tumor Surveillance
- Macrophage/Dendritic cell attack or antigen
presentation - CD8 cell-mediated cytotoxicity
- Antibody dependent cell mediated cytotoxicity
(ADCC) - Natural killer cells
17immunological surveillance
- CD8 Tc cells upon encounter with abnormally
expressed self antigen presented on MHC1
molecule, it will induce a cytotoxic response. - NK cells do not have antigen receptor, however,
they sense abnormal cell surface marker
expression, and upon such encounter it will
induce cytotoxic response. - Macrophage
- It has lectin on their surface, thus giving them
the capability to bind to carbohydrate residues. - Tumor cell express high number of carbohydrate
residues on their surface and upon encounter with
such a cell, it will induce a humoral response. - Cytokines
- Produced as a result of the recognition of the
tumor cell by one of the cells above, then binds
to cytokine receptors of the tumor cell, thus
induce appoptosis.
18 Tumors can both activate and suppress
immunity
Tumors can activate the immune response (ex.
expression of foreign antigen with MHCI) or
suppress the immune response (activation of T
regulatory cells that release IL-10 and TGF?)
the balance determines whether the cancer becomes
clinically relevant or not
Khong, H. T. et al. Nature Immunology 3, 999 -
1005 (2002)
19 Basic Tumor Immunosurveillance
- The presence of tumor cells and tumor antigens
initiates the release of danger cytokines such
as IFN? and heat shock proteins (HSP). - These cause the activation and maturation of
dendritic cells such that the present tumor
antigens to CD8 and CD4 cells - subsequent T cytotoxic destruction of the tumor
cells the occurs
Smyth, M. J. et al. Nature Immunology 2, 293 -
299 (2001)
20 MAC
Dendritic and Macrophage Presentation of Tumor
Antigen to CD4 Cells
Tumor cell or tumor derived antigen
MAC
MHC II
IL-1
Interferon
T helper Memory cell
T helper cell
IL-2
T helper effectorcell
Macrophages and dendritic cells can directly
attack tumor cells, or more commonly can express
exogenous antigens (TSAs or bits of killed tumor
cells) to CD4 cells
21Perforins, apoptotic signals
T cytotoxic memory cells
T Cytotoxic Cell Activity in Tumor Surveillance
MAC or B cell (APC)
T cytotoxic cell
MHC 1
T cytotoxic effector cells
Exogenous antigen
Cancer Cell
T cytotoxic cell
Endogenous antigen
22T cytotoxic memory cells
Perforins, apoptotic signals
MAC
Tumor antigen or tumor cell
T cytotoxic cell
MHC I
APC
T cytotoxic effector cells
MHC II
IL-1
Interferon
T helper Memory cell
T helper cell
IL-2
Perforins, apoptotic signals
1
T helper Effectorcell
Cancer Cell
T cytotoxic cell
T helper 2 cell
Generally ineffective tumor surveillance, but
some ADCC
IL-5
Endogenous antigen
IL-4
B Cell
Eosinophil
SUMMARY
23Antibody-dependent cell-mediated cytotoxicity
(ADCC)
MAC OR NK
Y
Y
Y
TARGET CELL
24NATURAL KILLER 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.
25Escape Mechanisms from Immuno Surveillance
- Conservation of cell-surface marker expression.
- Expression of FcRs Fc binds to constant region
of the produced antibodies ( and not to the
antigen-recognition site), thus preventing the
phagocytosis of the cell. - Secretion of the carbohydrate residues prevent
recognition by macrophages by occupying the
carbohydrate binding sites of the macrophage
before actual cell-to-cell contact. - Termination of cytokine receptor expression thus
making it impossible for cytokines to bind and
induce appoptosis (death).
26Lack of MHCI as a tumor escape mechanism
Defects in mechanisms of MHCI production can
render cancer cells invisible to CD8 cells
27Tumors can escape immunity (and immunotherapy) by
selecting for resistant clones that have occurred
due to genetic instability
28Immunoediting of cancer cells
Equilibrium refers to the selection for resistant
clones (red)
Escape refers to the rapid proliferation of
resistant clones in the immunocompetent host
Elimination refers to effective immune
surveillance for clones that express TSA
291) Tumor cell production of immune suppressants
such as TGF-?, 2) T regulatory cell
stimulation with production of immune
suppressants such as TGF- ?
Avoidance of tumor surveillance through release
of immune suppressants
1
2
Mapara Journal of Clinical Oncology.
22(6)1136-51, 2004
30Tumor cells induce apoptosis in T lymphocytes via
FAS activation
- Cancer cells express FAS ligand
- Bind to FAS receptor on T lymphocytes leading to
apoptosis
31TUMOR ESCAPE MECHANISMS
Or T regulatory cells
Or kill them
T regulatory cells
32Failure of Immune Response Against Tumor
- An effective tumor response to tumor can be
hampered by the following factors if effector
cells exist and tumors are antigenic,why arent
tumors rejected?) - a. Site of tumor. Some tumors arise in areas
not accessible to effector cells (eye and central
nervous system). - b. Antigenic modulation. Tumor cells may undergo
several antigenic changes. - c. Blocking factors. Immune complexes and
cytophilic antibodies can mask surface tumor
antigens or prevent binding by effector cells or
lytic antibodies.
33Antitumour Immunotherapy
34- A. Tumor cell vaccines - some patients have
circulating T cells directed against their tumor
cells, and in this setting the aim is to increase
their frequency. -
- Autologous or allogeneic tumor cells,
x-irradiated to prevent replication in vivo, or
mixed with an adjuvant to increase immunogenicity
have been tried.
35- B. Immunization with tumor-specific peptides -
Appropriate only for those tumors for which TAA
have been cloned and peptides synthesized. Thus,
presently of limited value clinically as vaccines
to induce anti-tumor responses.
36- C. Cytokine therapy - The aim is to augment the
antitumor response by increasing the levels of
particular cytokines. Among those that have been
tried are IL-2, IFN, GM-CSF, IL-7 and IL-12.
Problems are the short half-life, toxicity, and
non-specificity of cytokines.
37- D. Monoclonal antibodies - Have been used to
deliver immunotoxins, radioisotopes, or
chemotherapeutic drugs to tumor cells. New
approaches utilize bivalent antibodies containing
one arm that recognizes a T cell and another that
recognizes a TAA as a means to bring T cells
directly to the tumor site.
38- E. Gene therapy - Combines the concepts
underlying tumor cell vaccines with those
underlying cytokine therapy or to break
tolerance. This is accomplished by expressing
genes coding for cytokines, costimulatory
molecules, or MHC molecules.
39- F. Adoptive immunotherapy with antitumor T
cells, tumor-infiltrating lymphocytes (TIL), or
lymphokine-activated killer (LAK) cells -
Problems include difficulties in growing the
large numbers of cells required, loss of
antigenic specificity for T cells, or an altered
homing pattern following reinfusion.
40Immunodiagnosis
- Abs directed against tumor Ags are used in
- immuno-histochemical analysis of frozen sections
- sampled from cancer patients.
- Analysis of blood for tumor markers such as
a- - fetoprotein in hepatic carcinoma,
carcino-embrionic - antigen in colonic carcinoma has provided
valuable - diagnostic information.
- Abs are being used in the imaging of tumor
- tissues, using radio-opaque substances linked to
a - tumor specific Ab.