1. Medical Immunology Department of Immunology Yiwei Chu

2. DEPARTMENT OF IMMUNOLOGY Chapter 17 Immunity to tumors June, 21, 2010

3. DEPARTMENT OF IMMUNOLOGY Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy

4. DEPARTMENT OF IMMUNOLOGY Cancer is a major health problem worldwide and one of the most important causes of morbidity and mortality in children and adults.

5. DEPARTMENT OF IMMUNOLOGY Robin Bush The sister of George W. Bush, die from leukemia, at the age of 4. Walt Disney This famous animator, producer and co-founder of the corporation known as The Walt Disney Company died at the age of 65 from lung cancer, making him one of the most famous celebrities to have died from smoking. Paul Newman Paul Newman was of course a great actor, but was known well for his healthy line of food. He struggled with lung cancer, and passed away on September 26, 2008,at the age of 83.

6. DEPARTMENT OF IMMUNOLOGY General Features  Tumor express antigens that are recognized as foreign by the immune system of the tumor-bearing host.  Immune responses frequently fail to prevent the growth of tumors.  The immune system can be activated external stimuli to effectively kill tumor cells and eradicate tumors.

7. DEPARTMENT OF IMMUNOLOGY Tumor Antigen

8. DEPARTMENT OF IMMUNOLOGY  Immune responses frequently fail to prevent the growth of tumors  First, tumor cells are derived from host cells.  Second, the rapid growth and spread of tumors  Third, specialized mechanisms for evading host immune responses.

9. DEPARTMENT OF IMMUNOLOGY Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy

10. DEPARTMENT OF IMMUNOLOGY Tumor Antigen The earliest classification:  Tumor-specific antigen  Tumor-associated antigen

11. DEPARTMENT OF IMMUNOLOGY Tumor Antigen  Tumor-specific antigen Antigen that are expressed on tumor cells but not on normal cells were called tumor- specific antigens; some of these antigens are unique to individual tumors, whereas others are shared among tumors of the same type.

12. DEPARTMENT OF IMMUNOLOGY Tumor Antigen  Tumor-associated antigen Tumor antigens that are also expressed on normal cells were called tumor-associated antigens; in most cases, these antigens are normal cellular constituents whose expression is aberrant or dysregulated in tumors

13. DEPARTMENT OF IMMUNOLOGY Tumor Antigen

14. DEPARTMENT OF IMMUNOLOGY Tumor Antigen The modern classification is relies on the molecular structure and source of the antigen

15. DEPARTMENT OF IMMUNOLOGY Tumor Antigen

16. DEPARTMENT OF IMMUNOLOGY Tumor Antigen Type of antigenExamples of human tumor antigens Products of oncogenes, tumor suppressor genes Oncogenes: Ras mutations ( ∼ 10% of human carcinomas), p210 product of Bcr/Abl rearrangements (CML), overexpressed Her- 2/neu (breast and other carcinomas) Tumor supressor genes: mutated p53 (present in ∼ 50% of human tumors) Mutants of cellular genes not involved in tumorigenesis p91A mutation in mutagenized murine mastocytoma; various mutated proteins in melanomas recognized by CTLs Products of genes that are silent in most normal tissues Cancer/testis antigens expressed in melanomas and many carcinomas; normally expressed mainly in the testis and placenta Products of overexpressed genes Tyrosinase, gp100, MART in melanomas (normally expressed in melanocytes) Products of oncogenic viruses Papillomavirus E6 and E7 proteins (cervical carcinomas) EBNA-1 protein of EBV (EBV-associated lymphomas, nasopharyngeal carcinoma) SV40 T antigen (SV40-induced rodent tumors) Oncofetal antigensCarcinoembryonic antigen (CEA) on many tumors, also expressed in liver and other tissues during inflammation Alpha-fetoprotein (AFP) Glycolipids and glycoproteinsGM 2 GD 2 on melanomas Differentiation antigens normally present in tissue of origin Prostate-specific antigen Markers of lymphocytes: CD10, CD20, Ig idiotypes on B cells

17. DEPARTMENT OF IMMUNOLOGY Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy

18. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors  T lymphocytes  Antibodies  NK cells  Macrophages

19. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors  T lymphocytes The killing of tumor cells by CD8+ CTL

20. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors  T lymphocytes

21. DEPARTMENT OF IMMUNOLOGY

22. Immune Responses to Tumors  T lymphocytes

23. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors  Antibodies The killing of tumor cells by activating complement or by ADCC

24. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors Complement System

25. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors

26. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors  NK cells NK cells kill many types of tumor cells,especially cells that have reduces class I MHC expression and can escape killing CTLs.

27. DEPARTMENT OF IMMUNOLOGY engagement of inhibitory NK cell receptors such as KIR and CD94/NKG2 by class I MHC molecules delivers an inhibitory signal that counteracts the activation signal.

28. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors  NK cells

29. DEPARTMENT OF IMMUNOLOGY Immune Responses to Tumors  Macrophages Dual role of macrophages in tumor growth and angiogenesis:  They activate and present tumor antigens to T cells, which are then activated to kill tumor cells.  However, tumor cells are often capable of escaping the immune machinery. As the immune surveillance is not sufficient anymore, tumor-associated macrophages contribute to tumor progression.

30. DEPARTMENT OF IMMUNOLOGY Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy

31. DEPARTMENT OF IMMUNOLOGY The key of tumor growth, migration and metastasis is that tumor cells evade immune destruction, often called tumor escape. Turk MJ, J.Exp.Med. 2004, 200(6):771-782 Hori S: Science,2003, 299:1057-1061 Jun Shimizu et al: Nat. Immunology. 2002,3(2): 135-142 Shevach. EM: Nat Rev. Immunol. 2002, 2:389-400 Evasion of Immune Responses

32. DEPARTMENT OF IMMUNOLOGY Evasion of Immune Responses  Class I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs.  Tumor lose expression of antigen that elicit immune responses.  Tumors may fail to induce CTLs because most tumor cells do not express costimulators or class II MHC molecules.  The products of tumor cells may suppress antitumor immune responses.  Tumor antigens may induces may induce specific immunologic tolerance.

33. DEPARTMENT OF IMMUNOLOGY CD4+CD25+Treg ： Negative regulator  Existing a large amount of CD4+CD25+Tregs in TILs  Regrssion the tumorigenesis if deleting the CD4+CD25+Treg Tyler J. Curiel et al: Nature Medicine. 2004, 10(9):942-949 Zhang,L et al: N. Engl. J. Med. 2003, 348:201-213 Evasion of Immune Responses

34. DEPARTMENT OF IMMUNOLOGY Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy

35. DEPARTMENT OF IMMUNOLOGY Immunotherapy  History Cancer Immunosurveillance Hypothesis (Controversy to Resolution) ‘ Inheritable genetic changes must be common in somatic cells and a proportion of these change will represent a step toward malignancy. It is an evolutionary necessity that there should be some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character ’ ----- Sir MacFarlane Burnet, 1964 Fundamental Prediction: Immunodeficient individuals should show a significant increase in tumor incidence. However, ‘ Athymic-nude mice and normal mice showed no differences in either latent period or incidence of local sarcomas or lung adenomas within 120 days after administration of 3-methylcholanthrene at birth ’ ----- Stutman O, et al. Science 183(4124): 534. 1974

36. DEPARTMENT OF IMMUNOLOGY  27 years later …. Resolution  Increased Incidence of MAC-Induced Tumor Detected In Mice With Well-Defined Genetic Immunodeficiencies. Shankaran et al. Nature 410: 1107-1111 2001  An accumulation of immune cells at tumor sites correlates with improved prognosis. Zhang et al. N Engl J Med 348: 203-213 2003  First human melanoma tumor antigen (MAGE-1) was identified. T Boon et al. Science, Vol 254, Issue 5038, 1643-1647 1991 Immunotherapy

37. DEPARTMENT OF IMMUNOLOGY Immunotherapy Active immunotherapy Passive immunotherapy

38. DEPARTMENT OF IMMUNOLOGY Immunotherapy Active immunotherapy Vaccination Augmentation of host immunity to tumors with cytokines and costimulators

39. DEPARTMENT OF IMMUNOLOGY Immunotherapy Active immunotherapy------Vaccination 1.Killed tumor vaccine 2.Purified tumor antigens 3.Professional APC-based vaccines 4.Cytokine- and costimulator-enhanced vaccines 5.DNA vaccines 6.Viral vectors

40. DEPARTMENT OF IMMUNOLOGY Immunotherapy

41. DEPARTMENT OF IMMUNOLOGY Tumor Biopsy Vaccine Production Leukapheresis Dendritic Cells Co-culture + Fusion Myeloma cell Tumor Idiotype Protein As tumor specific- antigen + Immunization with Antigen-pulsed DCs Dendritic Cell- Based Vaccines Regression of Lymphoma following vaccination with Id-pulsed DC Levy R, Englman E, et al. Blood 2002, 90: 1517-1526 Immunotherapy

42. DEPARTMENT OF IMMUNOLOGY Immunotherapy Augmentation of host immunity to tumors

43. DEPARTMENT OF IMMUNOLOGY Immunotherapy Passive immunotherapy 1.Adoptive Cellular Therapy 2.Anti-tumor Antibodies

44. DEPARTMENT OF IMMUNOLOGY Immunotherapy Adoptive cellular therapy

45. DEPARTMENT OF IMMUNOLOGY

46. Immunotherapy Anti-tumor Antibodies Her-2/Neu, CD20, CD10, CEA, CA-125, GD3 ganglioside

47. DEPARTMENT OF IMMUNOLOGY Key notes  Concepts: TSA, TAA  Evasion of immune responses by tumors  Immunotherapy to tumors

48. DEPARTMENT OF IMMUNOLOGY Thank you! DEPARTMENT OF IMMUNOLOGY