1. Tumor Immunology Dr.Marián Sabol, PhD. P.J. Šafárik University, Medical Faculty, Institute of Medical Microbiology Tr. SNP 1, Košice, Slovakia

2. Introduction Current estimates project that one person in three will develop cancer and one person in five will die from cancer. (J.Kuby, 1992)

3. Immunologic perspective Cancer cells can be viewed as altered self cells that have escaped normal growth-regulating mechanisms.

4. The scope of lecture 1) Unique properties of cancer cells 2) Immune responses that develop to cancer cells 3) Escape of cancer cells 4) Therapies: clinical and experimental

5. Origin of Cancer -Cell growth regulation -Balance: cell renewal – cell death -Lifespan of cells -Cancer (tumor, neoplasm) -Cells which are no responsive to growth- control mechanisms -Clones that can expand to a considerable size (or number)

6. Malignant transformation Normal cells Transformed cells Proto-oncogenes Viral-oncogenes Cellular-oncogenes retroviral transduction mutagens, radiation, viruses, growth controlling proteins -growth factors -growth factors -GFR -GFR -signal transducers -signal transducers - intranuclear factors - intranuclear factors

7. Malignant transformation CML Philadelphia chromosome (reciprocal translocation)

8. Terminology Terminology 1) Benign -not capable of indefinite growth -does not invade the surrounding tissue extensively 2) Malignant -tumor that continues to grow -becomes progressively invasive -exhibit metastasis

9. Metastasis

10. Terminology Terminology Classification according embryonic origin of tissue from which tumor is derived 1) Carcinomas -endodermal and ectodermal tissues (skin, epithelial lining of internal organs and glands) 2) Sarcomas -mesodermal connective tissues (bone, fat, cartilage) 3) Leukemias and lymphomas -hematopietic cells of bone marrow

11. Malignant tumors Melanoma

12. Properties of Cancer Cells Cancer cells 1) clonally derived 2) changes in in vivo and in vitro growth 3) altered tissue-specific affinities 4) biochemical changes 5) chromosomal abnormalities

13. Tumor Antigens Tumor „Specific“ Ag 1) MHCI plus abnormal cell proteins (Brc-Alb, Philadelphia chromosome, CML) 2) MHCI plus viral proteins(EBV, SV40, polyoma virus) 3) Abnormal glycosylation 4) Idiotypes of myelomas and lymphomas Tumor Associated Antigens 1) Oncofetal Ag (alphafetoprotein – hepatoma, carcinoembryonic Ag – colon ca.) 2) Melanoma Ag (MAGE-1, Melan-A) 3) Her/neu Ag (GFR) 4) EPCAM (epithelial cell adhesion molecule, carcinomas) 5) Differentiaion Ag (CALLA: common acute lymphoblastoid leukemia antigen CD10 pre-B cells)

14. Anti-tumor immunity Anti-tumor immunity involve the same mechanisms as in anti-infection immunity, transplantation immunity or allergy. ComplementComplement LysozymeLysozyme CytokinesCytokines PhagocytosisPhagocytosis NK cellsNK cells AntibodiesAntibodies TcellsTcells

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16. Cytotoxic T cells

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19. Cancer Immunotherapy 1) Immune adjuvans -BCG (Bacillus Calmette Guérin) Mycobacterium bovis -mph >IL-1>Th, breast tumors, malignant melanoma -Corynebacterium parvum - DNCB (dinitrochlorobenzene) >>> DTH reaction

20. Cancer Immunotherapy 2) Cytokine therapy -IFN, IL-1, IL-2, IL-3, IL-4, IL-5, GM-CSF, TNF Interferons IFN alfa and beta - antiviral state, IFN gamma – activation IFN-alfa >> hematologic malignances, melanoma, renal cancer, breast cancer (low degree of malignity) -increase of tumor cell MHCI and mph MHCII >> CTL activity -IFN gamma >> increase the activity of Tc, NK, mph, Tumor necrosis factors - TNF alfa and beta > -decrease the proliferation of tumor cells and killing -decrease the angiogenesis - adverse reactions _______________ Systemic administration of high level of a given cytokine has been shown to lead to serious and even life threatening consequences.

21. Cancer Immunotherapy TIL and LAK cells - -in vitro Tc activation (X-irradiated tumor cells and IL-2) - -activation with IL-2 without tumor cells >> LAK cells (activated NK, NC cells) - -systemic IL-2 >> vascular leak syndrom, shock Tumor cell Vaccines - autologous tumor cells +BCG - engineered tumor cells which produce cytokines (IL-2, GM-CSF,..)

23. Tumor Immunology Thank you for attention.

24. Tumor Immunology