1. GENERAL IMMUNOLOGY PHT 324
Dr. Rasheeda Hamid Abdalla
Assistant Professor

2. TUMOR IMMUNITY

3. Objectives
Definition of cancer, carcinogenesis ,Classification of cancer ,and Carcinogens
Principal Targets of Genetic Damage
Tumor Immunity
Immune surveillance
Tumor antigens
Host Response to Tumors
Host immune response evasion by tumor cells
Immunodiagnosis&Immunotherapy

4. Definitions of Cancer and Carcinogenesis
Cancer: An abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). Cancer is not one disease. It is a group of more than 100 different and distinctive diseases. Cancer can involve any tissue of the body and have many different forms in each body area
Cancer cells arise from host cells via neoplastic transformation or carcinogenesis.

5. 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.

6. Classification of cancer
Carcinomas: epithelial origin involving the skin, mucous membranes, epithlial cells in glands
Sarcomas: cancer of connective tissue.
Lymphomas: T- B-cell, Hodgkin’s, Burkitt’s lymhomas; - solid tumors
Leukemias: disseminated tumors - may be lymphoid, myeloid, acute and chronic.

7. 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.

8. Principal Targets of Genetic Damage
Types of genes that control cancer
Four classes of regulatory genes
growth-promoting proto-oncogenes
growth-inhibiting tumor suppressor genes
genes that regulate programmed cell death (apoptosis)
genes involved in DNA repair

9. Cancer Cells Are Different
Escape normal intercellular communication
Allow for rapid growth
Increased mobility of cells
Invade tissues
Metastasis
Evade the immune system

10. Four mechanisms of oncogene activity to deregulate cell division

11. Tumor Immunity The immune system play a critical role in
distinguishing self from non-self molecules
Eliminating infectious agents
Immune system react to antigens that it recognizes as foreign
Tumor cells can be recognized by the immune system as non-self

12. Immune surveillance
Recognition and destruction of non-self tumor cells by the immune system (immunological resistance of the host against the development of cancer)

13. Evidence For Tumor Immunity
Regression of metastases after removal of primary tumor
Infiltrations of tumors by lymphocytes and macrophages
Lymphocyte proliferation in draining sites of cancer
Direct demonstration of tumor-specific T cells and antibodies in patients
Increased cancer risk after immunosuppression and immunodeficiency

14. Classification of Tumor Antigens
Two Categories:
based on their patterns of expression:
Tumor-specific antigens - present only on tumor cells and not on any normal cells
Tumor-associated antigens - present on tumor cells and also on some normal cells

15. Classification of Tumor Antigens
based on their molecular structure and source
Products of Mutated Oncogenes and Tumor Suppressor Genes
Products of other Mutated Genes
Over expressed or Aberrantly Expressed Cellular Proteins
Tumor Antigens Produced by Oncogenic Viruses
Oncofetal antigens
Altered glycolipids and glycoproteins
Cell type-specific differentiation antigens

16. TUMOR ANTIGENS Products of mutated genes
derived from the products of mutant proto-oncogenes, tumor suppressor genes, or other mutated genes
synthesized in the cytoplasm of tumor cells, and like any cytoplasmic protein, they may enter the class I MHC antigen processing pathway and be recognized by CD8+ T cells
In addition, these proteins may enter the class II antigen-processing pathway in antigen-presenting cells that have phagocytosed dead tumor cells, and thus be recognized by CD4+ T cells also

17. TUMOR ANTIGENS
Overexpressed or aberrantly expressed proteins
Tumor antigens may be normal cellular proteins that are abnormally expressed in tumor cells and elicit immune responses
Tyrosinase , MAGE(melanoma antigen gene )
is expressed on melanomas

18. TUMOR ANTIGENS
Oncofetal antigens
proteins that are expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues
Their main importance is that they provide markers that aid in tumor diagnosis

19. TUMOR ANTIGENS Oncofetal antigens Alpha fetoprotein(AFP):
Carcino-Embryonic Antigens (CEA)
- Normally expressed during fetal life on fetal gut
- GIT, pancreas, biliary system and cancer breast
Alpha fetoprotein(AFP):
- Normally expressed in fetal life
- hepatocellularcarcinoma

20. TUMOR ANTIGENS Antigens Produced By Oncogenic Viruses
Oncogenic viruses (eg; HPV,EBV, HBV) produce proteins that are recognized as foreign by the immune system

21. TUMOR ANTIGENS Altered Cell Surface Glycolipids and Glycoproteins
Expression of higher than normal levels and/or abnormal forms of surface glycoproteins and glycolipids
diagnostic markers and targets for therapy
These altered molecules include gangliosides, blood group antigens, and mucins

22. TUMOR ANTIGENS Altered Cell Surface Glycolipids and Glycoproteins
These include
CA expressed on ovarian carcinomas
CA expressed on carcinoma in pancreas & biliary tract
MUC-1 - expressed on breast carcinomas

23. TUMOR ANTIGENS Cell Type-Specific Differentiation Antigens
Tumors express molecules that are normally present on the cells of origin
Important for identifying the tissue of origin of tumors
These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types

24. TUMOR ANTIGENS Altered Cell Surface Glycolipids and Glycoproteins
Mucins are high-molecular-weight glycoproteins containing numerous O-linked carbohydrate side chains on a core polypeptide
Tumors often have dysregulated expression of the enzymes that synthesize these carbohydrate side chains, which leads to the appearance of tumor-specific epitopes on the carbohydrate side chains or on the abnormally exposed polypeptide core

25. TUMOR ANTIGENS Cell Type-Specific Differentiation Antigens
typically normal self-antigens, and therefore they do not induce immune responses in tumor-bearing hosts
For example, lymphomas may be diagnosed as B-cell-derived tumors by the detection of surface markers characteristic of this lineage, such as CD10 and CD20

26. Host Response to Tumors
Cellular Immunity
CTL (Cytotoxic T-lymphoctyes)
NK cells
Macrophages
Humoral Immunity
Antibody production by the host against host tumor cells or their constituents for tumor antigens

27. Host Response to Tumors
CTL (Cytotoxic T-lymphoctyes)
CTLs are the major immune defense mechanism against tumors
CTLs recognize peptides derived from cytoplasmic proteins that are displayed bound to class I major histocompatibility complex (MHC) molecules
CTLs play a protective role against virus-associated neoplasms (e.g., EBV- and HPV-induced tumors)

29. Host Response to Tumors
NK cells
Are capable of destroying tumor cells without prior sensitization – 1st line defense against tumor cells
After activation with IL-2 and IL-15, NK cells can lyse a wide range of human tumors
Recognize stress-induced antigens that are expressed on tumor cells and cells that have incurred DNA damage and are at risk for neoplastic transformation

30. Host Response to Tumors
Macrophages
Activated macrophages exhibit cytotoxicity against tumor cells in vitro
Activated macrophages may kill tumors by mechanisms similar to those used to kill microbes
(e.g., production of reactive oxygen metabolites or by secretion of TNF)

31. Host Response to Tumors
T cells, NK cells, and macrophages may collaborate in antitumor reactivity
interferon-γ, a cytokine secreted by T cells and NK cells, is a potent activator of macrophages

32. Host immune response evasion by tumor cells
Selective outgrowth of antigen-negative variants
loss or reduced expression of histocompatibility antigens
Lack of costimulation
Immunosuppression
Antigen masking
Apoptosis of cytotoxic T cells

33. Host immune response evasion by tumor cells
Selective outgrowth of antigen-negative variants
- during tumor progression, strongly immunogenic subclones may be eliminated
loss or reduced expression of histocompatibility antigens
- tumor cells may fail to express normal levels of HLA class I molecules, thereby escaping attack by cytotoxic T cells Such cells, however, may trigger NK cells

34. Host immune response evasion by tumor cells
Lack of costimulation
- sensitization of T cells requires two signals, one by a foreign peptide presented by MHC molecules and the other by costimulatory molecules
- although tumor cells may express peptide antigens with class I molecules, they often do not express costimulatory molecules

35. Host immune response evasion by tumor cells
Immunosuppression
Many oncogenic agents (e.g., chemicals and ionizing radiation) suppress host immune responses
Tumors or tumor products also may be immunosuppressive. For example, TGF-β, secreted in large quantities by many tumors, is a potent immunosuppressant

36. Host immune response evasion by tumor cells
Antigen masking
-The cell surface antigens of tumors may be hidden, or masked, from the immune system by glycocalyx molecules, such as sialic acid–containing mucopolysaccharides
Apoptosis of cytotoxic T cells
Some melanomas and hepatocellular carcinomas express FasL. It has been postulated that these tumors kill Fas-expressing T lymphocytes that come in contact with them, thus eliminating tumor-specific T cells

38. Immunodiagnosis Tumor antigens useful as tumor markers
released only from tumor tissue
Specific for a given tumor type
Has direct relationship to the tumor cell
Present in all patients with tumor
Tumors release antigen macromolecules that can be detected in vivo and in vitro

39. Immunodiagnosis Examples of tumor antigens used for tumor markers
Alpha-Fetoprotein
Beta-subunit of human chorionic gonadotropin (B-HCG)
Prostate-specific antigen (PSA)
CA 125
Radio-labeled monoclonal antibody B72.3
Carcinoembryonic Antigen (CEA)

40. Immunodiagnosis Immunohistochemistry
Categorization of undifferentiated malignant tumors
Determination of site of origin of metastatic tumors
Detection of molecules that have prognostic or therapeutic significance

41. Immunotherapy
Adoptive T cell therapy (AIT)
Passive immunotherapy using antibodies
Active-specific immunotherapy by using vaccines

42. Passive immunotherapy: mAbs
Herceptin: anti-HER-2/neu in breast cancer patients
Rituximab: anti-CD20 in patients with non-Hodgkin’s lymphoma
Limitations: clearance by soluble Ags, antigenic variation of the tumor, inefficient killing or penetration into the tumor mass