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Tumor Immunology
Masoud H. Manjili
Department of Microbiology & Immunology
Goodwin Research Laboratory-286
[email protected]
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
1. Genetic factors: hereditary cancers (10%):
retinoblastoma (Rb), breast cancer-1
(BRCA-1), BRCA-2
2. Environmental factors (mutation in
somatic cells): UV, chemicals, viral
infections (90%)
Cell Growth
Control of cell
growth
Growth-promoting
Proto-oncogenes
Growth-restricting
Tumor-suppressor genes
Molecular Basis of Cancer
Uncontrolled
cell growth
Conversion of protooncogenes 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
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
1) Transplantation: GVT
2) Active immunotherapy: cancer vaccines
3) 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
1) Transplantation: GVT
2) Active immunotherapy: cancer
vaccines
3) Passive immunotherapy:
antibodies
Cancer vaccines: cross
presentation of tumor antigens
Activation of naïve T cells
Tumor killing function
Signal I
T cells
Tumor
Signal II
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 tumorfree survival in patients with melanoma
Vaccination against oncogenic viruses
1. 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
1. Tumor-derived HSP vaccines: hsp70,
gp96
2. Recombinant HSP vaccines:
hsp70, hsp110, grp170
Immunotherapy of Cancer
1) Transplantation: GVT
2) Active immunotherapy: cancer vaccines
3) Passive immunotherapy: antibodies
Passive Immunotherapy
Abs against growth factor receptor e.g. IL-2R in HTLV1 induced Adult T cell leukemia
Anti-IL-2R Ab
IL-2R
IL-2
Abs specific for oncogene product e.g. Abs against
HER2/neu (Trastuzumab & Pertuzumab)
Tumor
dimerization
of HER-2/neu &
tumor proliferation
Tumor
Pertuzumab prevents
Homo- and hetero-dimerization of
HER-2/neu
Immunotoxins
ricin
iodine-131
Tumor evasion
HLA Loss
Total loss
HLA allelic loss
Haplotype 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.