1. Tumor Immunology Masoud H. Manjili
Department of Microbiology & Immunology
Goodwin Research Laboratory-286

2. Learning Objectives Etiology of cancer Immunotherapy of cancers
Tumor evasion

3. Tumor
Cells that continue to replicate, fail to differentiate into specialized cells, and become immortal
muscle, nerve, bone,
blood

4. Malignant: A tumor that grows indefinitely and spreads (metastasis)--also called cancer: kills host
Benign: A tumor that is not capable of metastasis: does not kill host

5. Types of Cancer
Carcinoma: arising from epithelial tissue, such as glands, breast, skin, and linings of the urogenital, digestive, and respiratory systems (89.3% of all cancers)
Leukemia: disease of bone marrow causing excessive production of leukocytes (3.4% of all cancers)
Lymphoma, Myeloma: diseases of the lymph nodes and spleen that cause excessive production of lymphocytes (5.4% of cancers)
Sarcoma: solid tumors of muscles, bone, and cartilage that arise from the embryological mesoderm (1.9% of all cancers)

6. Etiology of Cancer
Genetic factors: hereditary cancers (10%): retinoblastoma (Rb), breast cancer-1 (BRCA-1), BRCA-2
Environmental factors (mutation in somatic cells): UV, chemicals, viral infections (90%)

7. Cell Growth Control of cell growth Growth-promoting Growth-restricting
Proto-oncogenes
Growth-restricting
Tumor-suppressor genes

8. Molecular Basis of Cancer
Uncontrolled
cell growth
Conversion of proto-oncogenes to oncogenes:
amplification of c-erbB2 in breast cancer
mutation or amplification of c-ras in kidney and bladder cancers
chromosome translocation of c-myc in Burkitt’s lymphoma
Altered tumor-suppressor genes:
P53 mutation in prostate cancer: failure in cell cycle arrest or apoptosis of prostate tumors
Rb mutation in retinoblastoma
APC and DCC in colorectal cancer

9. Environmental Factors

10. Locus deletion

11. Series of mutations in oncogens and tumor suppressor genes in colorectal cancer
Mutations in one copy of oncogene and
both copies of tumor suppressor genes
contribute to malignant transformation

12. UV-induced Skin Cancers
Melanoma: metastatic, highly immunogenic, spontaneous rejection
Non-melanoma cancers:
1. Basal cell carcinoma: rarely spreads
2. Squamous cell carcinoma: can spread

13. Chemically-induced Cancers
Oxidants (inflammation, smoking) steal electron from DNA and increase the risk of many types of cancers such as lung and kidney cancers: anti-oxidants (vitamins A, C)

14. Virally-induced Cancers

15. Immunotherapy of cancer

16. Breast cancer is slow growing type of cancer

17. Adapted from Dunn et al, Immunity, 2004
hsp
APC
Adapted from Dunn et al, Immunity, 2004

18. Evidence for Tumor Immunity
Spontaneous regression: melanoma, lymphoma
Regression of metastases after removal of primary tumor: pulmonary metastases from renal carcinoma
Infiltration of tumors by lymphocytes and macrophages: melanoma and breast cancer
Lymphocyte proliferation in draining lymph nodes
Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.

19. Immunotherapy of Cancer
Transplantation: GVT
Active immunotherapy: cancer vaccines
Passive immunotherapy: antibodies

20. Allogeneic rejection of tumor
Tumors get rejected because of
a different MHC class I type

21. Hemetopoietic stem cell transplantation
1) Allogeneic stem cell transplantation: donor and recipients are HLA-matched (HLA-A, B,C, DR) but many are still affected by GVHD because of the reactivity against minor histocompatibility antigens
2) Autologous stem cell transplantation: No GVHD but relapse

22. Transplantation against tumors of immune system

23. Transplantation against tumors of immune system

24. Haploidentical transplantation: NK cells

25. Graft-versus-tumor (GVT), GVL, in patients with AML

26. Immunotherapy of Cancer
Transplantation: GVT
Active immunotherapy: cancer vaccines
Passive immunotherapy: antibodies

27. Cancer vaccines: cross presentation of tumor antigens
Activation of naïve T cells
Tumor killing function
Signal I
Signal II
T cells
Tumor

28. Tumor-specific Immune Response
Adaptive immune system differentiate
between normal and malignant cells
based on differential antigenic pattern of
tumors compared to normal cells B

29. Types of tumor antigens

30. Tumor antigens

31. MAGE-targeted vaccines result in tumor-free survival in patients with melanoma

32. Vaccination against oncogenic viruses
HPV recombinant vaccine against cervical cancer: humoral immunity, preventive vaccine
-- Gardasil: HPV6, 11, 16, 18
-- Cervarix: HPV16, 18
2. HBV recombinant vaccine against liver cancer: humoral immunity

33. Heat shock protein vaccines

34. Nicchitta, Nature Rev. Immunol., 2003

35. Heat shock protein cancer vaccines
Tumor-derived HSP vaccines: hsp70,
gp96
2. Recombinant HSP vaccines:
hsp70, hsp110, grp170

36. Immunotherapy of Cancer
Transplantation: GVT
Active immunotherapy: cancer vaccines
Passive immunotherapy: antibodies

37. Passive Immunotherapy
Abs against growth factor receptor e.g. IL-2R in HTLV-1 induced Adult T cell leukemia
Abs specific for oncogene product e.g. Abs against HER2/neu (Trastuzumab & Pertuzumab)
Anti-IL-2R Ab
IL-2R
IL-2
dimerization
of HER-2/neu &
tumor proliferation
Pertuzumab prevents
Homo- and hetero-dimerization of
HER-2/neu
Tumor
Tumor

38. Immunotoxins
ricin
iodine-131

39. Tumor evasion

40. HLA Loss Total loss Haplotype loss HLA allelic loss
HLA-A or B locus-specific loss

41. HLA loss renders tumor susceptible to NK-mediated apoptosis

42. MIC shedding and escape from NK cells

43. The immune System by Peter Parham,
Second edition, 2005; pg