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

2 Learning Objectives Etiology of cancer Immunotherapy of cancersTumor 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 hostBenign: 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-restrictingProto-oncogenes Growth-restricting Tumor-suppressor genes

8 Molecular Basis of CancerUncontrolled 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 cancerMutations in one copy of oncogene and both copies of tumor suppressor genes contribute to malignant transformation

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

13 Chemically-induced CancersOxidants (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, 2004hsp APC Adapted from Dunn et al, Immunity, 2004

18 Evidence for Tumor ImmunitySpontaneous 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 CancerTransplantation: GVT Active immunotherapy: cancer vaccines Passive immunotherapy: antibodies

20 Allogeneic rejection of tumorTumors get rejected because of a different MHC class I type

21 Hemetopoietic stem cell transplantation1) 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 CancerTransplantation: GVT Active immunotherapy: cancer vaccines Passive immunotherapy: antibodies

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

28 Tumor-specific Immune ResponseAdaptive 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 virusesHPV 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 vaccinesTumor-derived HSP vaccines: hsp70, gp96 2. Recombinant HSP vaccines: hsp70, hsp110, grp170

36 Immunotherapy of CancerTransplantation: GVT Active immunotherapy: cancer vaccines Passive immunotherapy: antibodies

37 Passive ImmunotherapyAbs 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 lossHLA-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