Cancer and the Immune System

1. Cancer and theImmune System Amar Bhatt Shirley Masand Jaime Warmkessel Immunology Chapter 22 April 22, 2003

2. A Look Ahead • Tumors and Metastasis • Oncogenes and Cancer Induction • Tumor Antigens • Tumors and the Immune Response • Immunotherapy

3. FATAL SYSTEM ERROR An exception error has occurred at AP222003C22. A virus has been detected. Quarantine has failed but the virus has been identified. Press the Any key to return to windows in safe sesame mode.

4. Cancer and theImmune System

5. Cancer “altered self-cells that have escaped normal growth regulation mechanisms” neoplasm: tumor benign vs. malignant metastasis: spreading of cancerous cells via blood or lymph to various tissues

6. Metastasis 22.1

7. Types of Cancers carcinoma: endodermal/ectodermal tissue leukemia/lymphoma: hematopoeitic stem cells sarcoma: mesodermal connective tissues

8. What makes cancer “cancer”? • decreased requirements for growth factors and serum • are no longer anchorage dependent • grow independently of density normal cells: eventually enter Go confluent monolayer CHECKPOINT FAILURE contact inhibition

9. Malignant Transformation • are like in vitro cancers • two phases • initiation (changes in genome) • promotion (proliferation)

10. Malignant Transformation • chemical and physical carcinogens • virally induced transformation • cultured tumors: good models for study • cancer cells are basically immortal

11. Oncogenes… oncogene: “cancer gene”; often found in viral genomes proto-oncogene: cellular counterpart which can be turned into an oncogene

12. What can go right? • induction of cellular proliferation • inhibition of cellular proliferation, a.k.a. tumor-suppressor genes • regulation of programmed cell death

13. Whatcangowrong? • chromosomal translocations • tandem repeats: HSRs • mutations in proto-oncogenes • viral integration • growth factors and their receptors

14. Induction of Cancer Fig. 22.2

15. Induction of Cancer

16. Lets Visualize! • http://science.education.nih.gov/supplements/nih1/cancer/activities/activity2_animations.htm

17. Tumors of the Immune System • Lymphomas • Solid tumors w/in lymphoid tissue (bone marrow, lymph nodes, thymus) • Hodgkin’s & non-Hodgkin’s • http://www.lymphomainfo.net/ • Leukemias • Proliferate as single cells • Acute or Chronic depending on the progression of disease • Acute- appear suddenly and progress rapidly; arise is less mature cells (ie ALL, AML) • Chronic- much less aggressive and develop slowly; mature cells (ie CLL and CML)

18. Tumor Antigens • TSTAs • Tumor Specific Transplantation Antigen • TATAs • Tumor Associated Transplantation Antigen

19. TSTAs • Unique to tumor cells • DO NOT occur on normal cells in the body • Novel proteins created my mutation presented on class I MHC • Can either be chemically/physically induced or virally induced tumor antigens

20. Chemically/Physically Induced • Specific Immunologic Response that can • Protect against later challenge by live cells • Of the same line but not other tumor-line • Cells. • Methylcholanthrene / UV light Fig 22.7

21. Virally Induced • Express tumor antigens shared by all tumors induced by the same virus • Burkitt’s Lymphoma • Epstein Barr • HPV Fig 22.9

22. TATAs • NOT unique to tumor cells • DO occur on normal cells in the body • So where’s the problem? • Fetal/adult presence • Concentration of Growth Factors and Growth Factor Receptors

23. TATAs cont’d • Oncofetal Tumor Antigens (AFP & CEA) • Normally appear in fetus before immunocompetence • Later recognized as non-self • Oncogene Proteins • Human Melanomas

24. Virally Induced Tumors • Virally induced tumors have the same antigens for each tumor caused by that virus. • HPV

25. Immune Response to Tumors • Mostly a cell-mediated response • NK Cells • Not MHC restricted • Fc receptor binds to antibody coated tumor cell  ADCC • Chedieak-Higashi syndrome • Macrophages • Not MHC restricted • Elicits ADCC • TNF-alpha • Immune Surveillance Theory

26. So, you have a tumor cell.Now what? • You need three things: • “See” the cancer • Ternary complex and costimulation by B7 • Activate lymphocytes • Release IL-2, IFN-gamma, and TNF-alpha • Cancer cells must be susceptible to killing • CTL lysis, macrophages, NK cells Info From: http://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.html#Introduction

27. But if the body has all these defenses, why do so many people still have cancer?

28. Conniving Cancer. • Bad antibodies? • Some antibodies do not protect against tumor growth, but also ENHANCE it. • Release of immunosuppressive cytokines • transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF) • Hide and go Seeking Antigen • Antigens actually seem to “hide” in the presence of antibody • Also, some cancer cells completely shed themselves of the antigen

29. Effect TGF-beta IL-10 VEGF Inhibition of T-cell growth + - + Inhibition of CTL differentiation + + + Inhibition of cytokine production + + - Induction of T-cell anergy + - - Downregulation of cytotoxic potential + + - Inhibition of antigen presentation + + - Shift in the Th1-Th2 balance towards Th2 + + - Downregulation of adhesion/costimulatory molecules + + - Resistance to CTL-mediated lysis - + - Source: Chouaib et al 1997

30. Conniving Cancer cont. • Reduction in Class I MHC Molecules

31. And the final blow… • Lack of Co- Stimulatory Signal

32. Can you tell me how to get...

33. ...How to get to Therapy Street?

34. Cancer Immunotherapy • Manipulation of Co-Stimulatory Signal • Enhancement of APC Activity • Cytokine Therapy • Monoclonal Antibodies • Cancer Vaccines

35. Manipulation of Co-Stimulatory Signal • Tumor immunity can be enhanced by providing the co-stimulatory signal necessary for activation of CTL precursors (CTL-Ps) • Fig. 22.11a

36. Manipulation of Co-Stimulatory Signal Cont. • Basis for Vaccine • Prevent metastasis after surgical removal or primary melanoma in human patients

37. Enhancement of APC Activity • GM-CSF (Granulocyte-macrophage colony-stimulating factor) remember: CSFs are cytokines that induce the formation of distinct hematopoietic cell lines • Fig 22.11b

38. Cytokine Therapy • Use of recombinant cytokines (singly or in combination) to augment an immune response against cancer • Via isolation and cloning of various cytokine genes such as: • IFN-α, β, and γ • Interleukin 1, 2, 4, 5, and 12 • GM-CSF and Tumor necrosis factor (TNF)

39. Cytokine Therapy Cont. I. Interferons • Most clinical trials involve IFN-α • Has been shown to induce tumor regression in hematologic malignancies i.e. leukemias, lymphomas, melanomas and breast cancer • All types of IFN increase MHC I expression • IFN-γ also has also been shown to increase MHC II expressionon macrophages and increase activity of Tc cells, macrophages, and NKs

40. Cytokine Therapy Cont. • Tumor Necrosis Factors • Kills some tumor cells • Reduces proliferation of tumor cells without affecting normal cells How? • Hemorrhagic necrosis and regression, inhibits tumor induced vascularization (angio-genesis) by damaging vascular endothelium

41. Cytokine Therapy Cont. • In Vitro-Activited LAK & TIL cells A. Lymphocytes are activated against tumor antigens in vitro • Cultured with x-irradiated tumor cells in presence of IL-2 • Generated lymphokine activated killer cells (LAKs), which kill tumor cells without affecting normal cells

42. In Vitro-Activated LAK and TIF cells Cont. B. Tumors contain lymphocytes that have infiltrated tumor and act in anti-tumor response • via biopsy, obtained cells and expanded population in vitro with • generated tumor-infiltrating lympho- cytes (TILs)

43. Monoclonal Antibodies • Anti-idiotype • Growth Factors -HER2 • Immunotoxins

45. Cancer Vaccines • Genetic • Biochemical

46. HPV Human Papilloma Virus • E6 • E7

47. From Normal to Abnormal:

48. For more info • HPV • Cancer Vaccines

49. This Day Has Been Brought to you By the Letter… C C is for Cancer!