Tumor Immunology Masoud H. Manjili Department of Microbiology & Immunology Goodwin Research Laboratory-286 mmanjili@vcu.edu

Learning Objectives Etiology of cancer Immunotherapy of cancers Tumor evasion

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

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

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)

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%)

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

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

Environmental Factors

Locus deletion

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

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

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)

Virally-induced Cancers

Immunotherapy of cancer

Breast cancer is slow growing type of cancer

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

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.

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

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

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

Transplantation against tumors of immune system

Transplantation against tumors of immune system

Haploidentical transplantation: NK cells

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

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

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

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

Types of tumor antigens

Tumor antigens

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

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

Heat shock protein vaccines

Nicchitta, Nature Rev. Immunol., 2003

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

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

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

Immunotoxins ricin iodine-131

Tumor evasion

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

HLA loss renders tumor susceptible to NK-mediated apoptosis

MIC shedding and escape from NK cells

The immune System by Peter Parham, Second edition, 2005; pg. 412-431.