1. Immunological aspect of tumor
Ahmad Shihada Silmi
Hematologist & Immunologist
IUG

2. Definition
A tumor erupts as a result of a mutation or damage to one cell leading to abnormal proliferation.

3. Once 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.

4. Four mechanisms of oncogene activity to deregulate cell division

5. A closer look at p53

6. Oncogenesis 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

7. Cancer cells are different
Escape normal intercellular communication
Allow for rapid growth
Increased mobility of cells
Invade tissues
Metastasis
Evade the immune system

8. Tumors and the Immune System
Clinical tumors, by definition, have been able to evade the immune response
Deletional Tolerance
Nondeletional Tolerance

9. QUESTIONS 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?

10. EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE RESPONSE

11. Tumor 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

12. Tumor 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

13. TUMOR OVEREXPRESSION OF NORMAL AG

14. 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)

15. CEA TUMOR ANTIGEN IN COLON CANCER
1000
100
CEA (ng/ml) 10
Normal Range
100
200
300
400
Surgical Removal of Tumor
Clinical Manifestations Appear
Time in Days 

16. Tumor Surveillance
Macrophage/Dendritic cell attack or antigen presentation
CD8 cell-mediated cytotoxicity
Antibody dependent cell mediated cytotoxicity (ADCC)
Natural killer cells

17. immunological 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, (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, (2001)

20. 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 (TSA’s or bits of killed tumor cells) to CD4 cells

21. T Cytotoxic Cell Activity in Tumor Surveillance
Perforins, apoptotic signals
T Cytotoxic Cell Activity in Tumor Surveillance
T cytotoxic
memory cells
MAC or
B cell
(APC)
T cytotoxic cell
MHC 1
T cytotoxic
effector cells
Exogenous antigen
Cancer Cell
T cytotoxic cell
Endogenous antigen

22. SUMMARY APC MAC Cancer Cell T cytotoxic Tumor antigen or tumor cell
Perforins, apoptotic signals
T cytotoxic
memory cells
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-4
IL-5
Endogenous antigen
B Cell
Eosinophil
SUMMARY

23. Y Y Y Antibody-dependent cell-mediated cytotoxicity (ADCC) MAC OR NK
TARGET CELL

24. Target cell (infected or cancerous)
NATURAL 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. NK
Target cell (infected or cancerous)
Perforin and enzymes
killer activating receptor

25. Escape 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).

26. Lack of MHCI as a tumor escape mechanism
Defects in mechanisms of MHCI production can render cancer cells “invisible” to CD8 cells

27. Tumors can escape immunity (and immunotherapy) by selecting for resistant clones that have occurred due to genetic instability

28. Immunoediting 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

29. Avoidance of tumor surveillance through release of immune suppressants1 2
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): , 2004

30. Tumor cells induce apoptosis in T lymphocytes via FAS activation
Cancer cells express FAS ligand
Bind to FAS receptor on T lymphocytes leading to apoptosis

31. TUMOR ESCAPE MECHANISMS
Or T regulatory cells
Or kill them
T regulatory cells

32. Failure 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 aren’t 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.

33. Antitumour 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.

40. Immunodiagnosis immuno-histochemical analysis of frozen sections
• 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.