Chapter 20 Tumor Immunology

1. Chapter 20 Tumor Immunology

2. Chapter 20 Tumor Immunology Contents Introduction PartⅠTumor antigens PartⅡ Immune response to tumors Part Ⅲ Mechanism of tumor escape from immune surveillance PartⅣ Immunotherapy of tumors

3. Introduction • Tumor immunology is mainly to study the immunogenicity of tumor and the mechanism of immune response to tumor, to demonstrate the relationship between the status of immune system and the generation, development of tumor, to explore the method of tumor diagnosis, therapy and prevention. • Immunosurveillance

4. PartⅠ Tumor antigens • Tumor antigens: Refer to all newly expressed antigens or over expressed antigens during the generation and development of the tumor.

5. Ⅰ.Classification of tumor antigens Base on their patterns of expression: • Tumor specific antigen (TSA) • Tumor associated antigens (TAA)

6. 1.Tumor-specific antigens (TSA) TSA: Antigens that are only expressed on tumor cells but not on normal cells. high specificity. Tumor high-specific antigens TSA---only expressed on one kind of tumor, induced by physiochemical factors, such as X-ray Tumor low-specific antigens TSA---expressed on more than one kind of tumor, induced by virus

7. Discovery of tumor specific transplantation antigens, TSTA 化学致癌剂甲基胆蒽(methyl-cholanthrene,MCA)

8. Conclusion from this experiment • Tumors express antigens that are recognized as foreign by the immune system of the tumor-bearing host. • Immune response frequently fail to prevent the growth of tumors. • The immune system can be activated by external stimulator to effectively kill tumor cells and eradicate tumors.

9. 2.Tumor-associated antigens,TAA • Antigens that are also expressed on normal cells, but high expressed on tumor cells. Without tumor specificity: CEA, AFP

10. Ⅱ.Common human tumor antigens • Embryonic antigens • Tumor antigens induced by viruses • proteins coded by Mutated oncogene or suppressor oncogene • TATAS expressed on human melanoma cells

11. 1. embryonic antigens embryonic antigens are proteins that are express at high levels on cancer cells and in normal developing fetal, but peter out or very low level in adult. • Their main function is that they provide markers that aid diagnosis of tumor. Carcinoembryonic antigen (CEA) alpha-fetoprotein (AFP)

12. (1) Carcinoembryonic antigen (CEA) • High CEA level is normally restricted to cells of the gut, pancreas, and liver in the course of 2-6 months of gestation, and low level is found in serum of normal adult(<5g/ml). • CEA level of serum is increased in many carcinomas ,such as the colon, pancreas, stomach, and breast. • The level of serum CEA is used to monitor the persistence or recurrence of the tumors after treatment.

13. CEA levels in normal individuals are below 2.5 ng/ml, but it increases significantly in certain malignancies, particularly colo-rectal cancers. It may also rise in some nonmalignant conditions (e.g., chronic cirrhosis, pulmonary emphysema, heavy smoking). Levels 4-5-fold of normal have been used to predict recurrence of colo-rectal tumors.

14. Carcinoembryonic antigen:clinical use • Adjunct in diagnosis • Staging and prognosis • Monitoring response to therapy • Detection of tumor recurrence

15. Carcinoembryonic antigen:clinical use

16. (2) alpha-fetoprotein (AFP) • AFP is a circulating glycoprotein normally synthesized and secreted by the yolk sac and liver of fetal. • Serum levels of AFP is very low in serum of adult (≤20ng/ml), and the concentration of AFP is up to 500ng/ml in serum of patients with hepatocellular carcinoma. • higher rise in this protein is used for monitoring hepatomas and testicular cancers. AFP level may also be raised in some nonmalignant conditions, such as cirrhosis, hepatitis and other forms of liver damage.

17. Alpha fetoprotein: concentrations • Normal concentration: <20 ng/ml • Abnormal concentrations • 100-350 possible hepatoma • 350-500 probable hepatoma • 500-100 likely hepatoma • >1000 HEPATOMA

18. 2. Tumor antigens induced by viruses: • HBV------ liver cancer • HPV------ cervical carcinoma • EBV------ B cell lymphoma and nasopharyngeal carcinoma

19. 3. Products of mutated genes: • Some tumor antigens are produced by mutated genes, such as suppressor oncogenes p53 and pro-oncogene ras

20. Some patients with cancer have circulating CD4+ and CD8+T cells that can respond to the products of mutated genes such as Ras and P53. • Furthermore, in animals, immunization with mutated Ras or P53 proteins induces CTLs and rejection responses against tumors expressing these mutants.

21. Overexpressed cellular proteins and abnormally expressed proteins: • gp100, MAGE in melanomas • Cancer-testis antigens

22. PartⅡ Mechanism Immune Response T cells: αβT, γδT NK cells • Cellular immunity Macrophages Dendritic cells • Humoral immunity

23. Ⅰ.Cell-mediated Immune Response • T cells • NK cells • Macrophages(MΦ) • Dendritic cells (DCs)

24. 1. T lymphocytes: • T cells The principal mechanism of tumor immunity is killing of tumor cells by CTL Tumor antigens DC cross presentation CD4+Th cells CD8+T （CTL）

27. (2) T cells Non-classⅠMHC restriction Its target cells are not hypersensitive to NK cells First line of defence of immune surveillance

28. 2. NK cells: • NK cells are broad-spectrum killer cells • It can kill target cells with low level or non MHC class Ⅰmolecule. • First line of defence of immune surveillance

29. NK细胞识别MHCI类分子的受体 KIR2DS KIR2DL KIR2D KIR3D DAP12 ITAM 杀伤细胞免疫球蛋白样受体(KIR)（MHC-G） ITIM KIR2DL KIR2DS CD94/NKG2A：ITIM CD94/NKG2C：连接DAP12 -ITAM 杀伤细胞凝集素样受体（KLR） （HLA-E-9肽）

30. activated Tumor cell

31. 3. Macrophages(MΦ) ① APC ② release of lysosomal enzymes, reactive oxygen intermediates, nitric oxide ③ ADCC ④ secrete cytokines 4. Dendritic cells: ①APC------Induce adaptive immune response ② Inhibit tumor growth directly

32. Antibodies: ① Activating complement ② ADCC③ Opsonization Ⅱ. Humoral immune responses

33. Antitumor Effector Mechanisms CTL NK cell Tumor cell Humoral Mechanisms Macrophage Kumar et al. Basic Pathology 6th ed. Figure 6-32

34. PartⅢ Mechanism of Tumor Immune Escape Factors related to tumor cells Factors related to the host’s immune system

35. Ⅰ. Factors related to tumor cells 1.low immunogenicity of tumor antigens and antigenic modulation (1) low immunogenicity of tumor antigens The failure of immunosurveillance may be the fact that in the early development of a tumor, the amount of antigen may be too small to stimulate the immune system.

36. Escape from immunosurveillance Lack of Neo-antigens

37. (2) antigenic modulation: is a phenomenon that cell-surface tumor antigens are decrease or lose because of attack of host’s humoral immune.

38. 2. covering or blocking of tumor antigens on the surface of the tumor cells

39. 3. Diminution or absence of MHC class I molecule • 4. Lack of co-stimulatory molecule on the surface of tumor cells • 5. Immune inhibitors secreted by tumor cells

41. Escape from immunosurveillance

42. Ⅱ.Factors related to host’s immune system • 1. Immunodeficiency • 2. Suppressing immune function by tumor directly or indirectly

43. Parts Ⅳ immunotherapy of tumor • Active immunotherapy • Target immunotherapy • Adoptive immunotherapy • Cytokine therapy • genetherapy

44. Escape from immunosurveillance Tumors shed their neo-antigens

45. Factors related to host: • Poor immune function • Tumor inhibit immune function of host

46. Escape from immunosurveillance Tumors secrete Immunosuppressive molecules

47. PartⅤ Immunotherapy of tumors • Active immunotherapy • Target immunotherapy • Adoptive immunotherapy • Cytokine therapy • Gene therapy

48. Stimulation of active host immune responses to tumors: • Vaccination with tumor cells and tumor antigens, or with APC. • Augmentation of host immunity to tumors with cytokines and costimulators • Nonspecific stimulation of the immune system

49. Vaccination with tumor cells and tumor antigens