118/2/2015 Cancer & the Immune System Hugh B. Fackrell

228/2/2015 Cancer & the Immune System l Assigned Reading l Content Outline l Performance Objectives –Key terms –Key Concepts l Short Answer Questions

338/2/2015 Assigned Reading l Janis Kuby’s Immunology 4th Ed Chapter: 22 pp l Janis Kuby’s Immunology 3rd Ed l Chapter: 24 pp

448/2/2015 Content Outline l Origins & Terms l Malignant Transformation l Tumours of the Immune System l Tumour Antigens l TATAs on human melanomas l Immune Response to Tumours l Tumour Evasion of Immune Response l Cancer Immunotherapy

558/2/2015 Origins & Terms

668/2/2015 Benign vs malignant

778/2/2015 Distribution of Cancer

888/2/2015 Growth of Breast Cancer Diameter of Tumour (mm) Tumour Cell doubling Tumour visible by X rays Tumour first palpable Death of Patient 10 8 cells 10 9 cells cells

998/2/2015 Altered Growth Properties

10 8/2/2015 Localized Benign Tumour

11 8/2/2015 Tumour Invasion of Basal Lamina

12 8/2/2015 Metastasizes to Other Sites

13 8/2/2015 Tumour Antigens l Tumour specific Antigens –chemically induced –virally induced l Tumour associated antigens –oncofetal tumour antigens –oncogene proteins

14 8/2/2015 TSTA vs TATA

15 8/2/2015 Radio labelled anti CEA

16 8/2/2015 Genes for TSTAs

17 8/2/2015 Malignant Transformation l Oncogenes l Induction of cell proliferation l Inhibition of cell proliferation l Regulation of apoptosis

18 8/2/2015

19 8/2/2015

20 8/2/2015 Chromosomal translocations

21 8/2/2015 Tumour Induction

22 8/2/2015 Induction of Tumours

23 8/2/2015 Tumours of the Immune System

24 8/2/2015

25 8/2/2015 TATAs on human melanomas

26 8/2/2015 TATAs on human melanomas

27 8/2/2015 Immunity to Polyoma virus(1)

28 8/2/2015 Immunity to Polyoma virus(2)

29 8/2/2015 Immunity to Polyoma virus (3)

30 8/2/2015 Immunity to Polyoma Virus (4)

31 8/2/2015 Immune Response to Tumours l NK cells & macrophages l Immune surveillance theory

32 8/2/2015

33 8/2/2015

34 8/2/2015 Tumour Evasion of Immune Response l Immunologic enhancement l Modulation of tumour antigens l Reduce MHC-I l No co-stimulatory signal

35 8/2/2015

36 8/2/2015

37 8/2/2015 Tumor Escape

38 8/2/2015 Cancer Immunotherapy l Modify Co-stimulatory signal l Enhance APC activity l Cytokine therapy l MABs l Tumour cell vaccines

39 8/2/2015 Cancers Treatable by Bone Marrow Transplants Allogenic/syngenic Transplant –Breast cancer –aplastic anemia –leukemia –ALL –CML –Myeolodysplasia –multiple myeloma –Non- Hodgkin’s lymphoma –Hodgkin’s disease Autologous Transplants –Leukemia –AML –ALL –Multiple Myeloma –Non Hodgkin’s lymphoma –Hodkin’s disease –Solid tumours –Breast –ovarian –testicular –Neuroblastoma

40 8/2/2015

41 8/2/2015 Transfect co stimulartory signal

42 8/2/2015 Transfect with GM-CSF

43 8/2/2015 Lak cells & IL-2

44 8/2/2015 Mabs to B cell Lymphoma

45 8/2/2015 Tumour Cell Vaccine Immune Response to MCA or PV Transplant killed cells of MCA induced sarcoma A l Challenge with Sarcoma A- No Growth l Challenge with Sarcoma B- growth Transplant killed cells of Polyoma Virus induced sarcoma A l Challenge with sarcoma A no growth l challenge with sarcoma B no growth l SV40 induced sarcoma C- growth

46 8/2/2015

47 8/2/2015 DONE!!!

48 8/2/2015

49 8/2/2015

50 8/2/2015

51 8/2/2015

52 8/2/2015

53 8/2/2015

54 8/2/2015

55 8/2/2015

56 8/2/2015

57 8/2/2015

58 8/2/2015

59 8/2/2015

60 8/2/2015 Performance Objectives

61 8/2/2015 Key Terms l antibody dependent cell mediated cytotoxicity (ADCC), benign tumour, cancer, l carcinogens, proto oncogens, immune surveillance, Specific immunotherapy, l non specific immunotherapy, immunotoxins,Lymphokine activated killer cell(LAK),

62 8/2/2015 l neoplasm, oncofetal antigens, oncogens, tumour, tumour associated antigens, l tumour associated transplantation antigens, tumour specific antigens, l tumour specific transplantation antigens

63 8/2/2015 Key Concepts l Differentiate between a benign tumour and a malignant tumour. l Describe the concept of immunosurveillance l Describe the different ways that tumours can camouflage themselves to evade immune defenses, l Discuss the advantages of immunotherapy over other forms of cancer therapy.

64 8/2/2015 l Distinguish between specific and nonspecific immunotherapy with the use of specific examples. l Describe immunotoxins. l Describe the development of humanized antibodies to tumour antigens l Evalulate the contribution of T cells, NK cells, Macrophages, and B cells to tumour immunity.

65 8/2/2015 l Distinguish between tumour specific transplantation antigens and tumour assoicated transplantation antigens. l Describe oncofetal antigens.

66 8/2/2015 Short Answer Questions

67 8/2/2015 l Explain how some cancer cells that can make TGF-beta are immunosuppressive. l Tumours and transplants are similar to one another,yet very different. Explain this observation in the context of what the immune system recognizes and the result of this recognition. l The qualities of proliferation and differentiation are essentially all that distinguishes a normal cell from a cancer cell. Explain.

68 8/2/2015 l Design an experiment using mice that proves that the immune system provides immunity against tumours. l Distinguish between tumour-specific transplantation antigens (TSTA) and tumour associated transplantation antigens (TATA). l Design an experiment to show Tumour associated Transplantation Antigens (TATA). l What is the main difference separating cell surface antigens from chemically induced and virually induced cancers?

69 8/2/2015 l Speculate on why this difference leads to difficulty in designing anticancer vaccines. l What are oncofetal antigens? Are they important in tumour immunity? Why? l What is immune surveillance? l All evidence for immune surveillance is indirect. Speculate on how you could get direct evidence.

70 8/2/2015 l What immune cells play a role in tumour rejection? Briefly describe how each accomplishes this task. Include such things as cytokines, perforins, ADCC etc. l Cancers camouflage themselves to evade antitumour defenses. Pick three possible forms of camouflage that you think are most important, describe them and state why you think they are most important. l What are immunotoxins?

71 8/2/2015 l Surgery, radiation and chemotherapy are the methods most widely used to treat cancer patients. What are the problems with this regimen, and how could immunotherapy overcome these problems. l Distinguish between specific and nonspecific immunotherapy.