Ch' 21' Cancer and the Immune System

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Ch. 21. Cancer and the Immune System What is
cancer? What is the immune response to
cancer? What are the prospects for immune
therapies?
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Cancer cells are out of control! Usually derived
from a single cell, forming a neoplasm, or
tumor Benign tumors are noninvasive malignant
tumors can invade and spread (metastasis) Cancer
s are classified according to their
origin Carcinomas vs blood cell cancers
leukemias and lymphomas
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How do cells become transformed into malignant
cells? Radiation Carcinogens Viruses expression
of oncogenes (aberrant versions of
proto-oncogenes)
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Types of regulatory genes Proto-oncogenes-
induce proliferation in various ways Tumor
suppressors- inhibit cell proliferation Regulator
s of apoptosis Defects in any of these can lead
to uncontrolled cell growth
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Mutations accumulate in these cells as they are
gradually converted to malignant cells Transloca
tions are associated with certain specific tumors
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Immune system tumors Solid or systemic? Acute or
chronic? Immature or mature cells? Myelocytic or
lymphocytic?
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Tumor-specific antigens (TSTA) - found only on
tumors chemical or physical carcinogens some
viruses e.g., ATLL, HPV Adult T-Cell
Leukemia/Lymphoma Human Papilloma Virus (types
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be gene products that normally are not
expressed (or at the abnormal levels seen in
cancer) Can these be isolated and used as
vaccines? Diagnosis? Therapy?
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Most tumor antigens are NOT unique to
tumors Often these are fetal proteins (e.g.,
growth factor receptors) CEA- carcinoembryonic
antigen AFP- alpha-fetoprotein Oncogene proteins
as tumor antigens Neu on human breast cancer
cells TATAs on human melanomas MAGE1,
MAGE-3, BAGE, GAGE-1, GAGE-2. Some shared
with other tumors
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Immune response to tumors Abs CMI (after
all, its altered self) Cell-mediated response
of major importance CTLs, NK cells (with or
w/o ADCC), activated macrophages regression
(lytic enzymes, ROI, RNI, TNF-alpha) Many
tumors reduce MHC Class I expression NK cells can
kill these Also macrophages add NK cells can
attack antibody-coated tumor cells (ADCC) Immune
surveillance?
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Tumors can evade immune response Anti-tumor
antibody can block T cell responses (enhance
tumor growth) Tumors can modulate antigens Ag
modulation (Abs bind to Ag on leukemic cells,
induce capping, endocytosis of Ag, shedding
of Ag-Ab complexes) Tumors can reduce MHC Class
I expression (selection escape CTL
recognition) Tumors can reduce second signal
expression (no B7 -gt clonal anergy)
im
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Strategies for immunotherapy adjuvant or
cytokine Make cells more immunogenic better CTL
activation vaccine made up of
cells? Enhancement of APC activity can modulate
tumor immunity BCG attenuated Mycobacterium
bovis mouse dendritic cells incubated with
GM-CSF and tumor fragments, then into
animal, activate anti-tumor Th and CTLs
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Cytokine therapy Many have been tried thanks
to recombinant DNA technology interferons (incr.
MHC I, MHC II), tumor necrosis factors (TNF),
IL-2, -4, -6, -12 GM-CSF Problems complexity
of cytokine interactions hard to
administer short half-life serious side effects
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LAK cells (lymphokine-activated killer
cells) grow blood cells in high levels of
IL-2 produce mostly NK cells (NOT
tumor-specific) TILs (tumor-infiltrating
lymphocytes) may have more tumor-specific
activity and need less IL-2
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Monoclonal antibodies are useful in treating
some tumors Idiotype-specific for B-cell
lymphoma Levy (Stanford) Humanized Anti-HER
2 for HER2-receptor-bearing breast
cancer Immunotoxins mAb conjugated to ricin
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Cancer vaccines? Antigenic peptides
(tumor-specific and immunogenic Delivery
(recombinant vaccines) Will they be effectively
presented to T cells? Some viral vaccines (e.g.,
against HPV) may be helpful There is much to be
done.